Published online before print November 12, 2007, doi: 10.1161/HYPERTENSIONAHA.107.092866
(Hypertension. 2008;51:1.)
© 2008 American Heart Association, Inc.
Brief Reviews |
Maintaining Equilibrium by Selective Targeting of Cyclooxygenase Pathways
Promising Offensives Against Vascular Injury
From the Departments of Pathology and Laboratory Medicine (R.S.D., R.K.U., B.D.L., D.P.H.) and Pharmacology (S.S.G.) and the Center of Vascular Biology (R.S.D., R.K.U., B.D.L., S.S.G., D.P.H.), Weill Cornell Medical College, New York, NY.
Correspondence to David P. Hajjar, Department of Pathology and Laboratory Medicine, Center of Vascular Biology, Room A626, Weill Cornell Medical College, 1300 York Ave, New York, NY 10021. E-mail dphajjar{at}med.cornell.edu
 |
Introduction |
|---|
 Top Introduction The Prostaglandin Biosynthesis...Targeting Oxidative Stress and...Future Therapeutic Potentials...References |
|---|
Cardiovascular disease is the leading cause of death in most Western countries. Vascular abnormalities associated with cardiovascular disease are attributable to a variety of risk factors, including hypercholesterolemia, hypertension, hyperglycemia, lipotoxicity, obesity, aging, and tobacco smoke.1,2 Importantly, altered ·NO bioavailability is a major underlying mechanism linking each of these risk factors. Indeed, the endothelium is recognized as a pivotal regulator of vascular function by maintaining homeostatic levels of ·NO and prostanoids derived from arachidonic acid (AA) metabolism.3
Eicosanoids, synthesized from unsaturated fatty acids, are biologically active molecules that play a wide range of regulatory roles in the cardiovascular, renal, immune, and gastrointestinal systems.4 Alterations in their biosyntheses can promote hypertension, diabetes, and, in particular, atherosclerosis, an inflammatory disease characterized by the accretion of fat-laden plaques in the arterial wall that can lead to vasoocclusive events. During atherogenesis, eicosanoid production (from the cyclooxygenases [COXs], lipoxygenases [LOXs], and cytochrome P450s pathways) is altered by mechanisms that are not yet well understood. The dichotomous nature of eicosanoids requires that their balance is maintained, and, as such, these pathways are a relevant therapeutic target against cardiovascular disease.5 Thus, it is now appreciated that cardiovascular disease can be triggered by an absolute deficiency of ·NO and/or an imbalance between "beneficial" and "harmful" eicosanoids in the vasculature and that these pathways are mutually interactive. In this review we consider pharmacological therapies possessing the potential for greater safety and efficacy than nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of chronic vasoinflammatory conditions.
|
The Prostaglandin Biosynthesis Quandary |
|---|
|
TopIntroductionThe Prostaglandin Biosynthesis...Targeting Oxidative Stress and...Future Therapeutic Potentials...References |
|---|
Fundamental physiological distinctions are now recognized for the structurally similar enzymes, COX-1 and COX-2. Constitutively expressed COX-1 is found in almost all of the tissues where it subserves diverse physiological functions. Basal expression of COX-2 is limited to the kidney, brain, and reproductive system4 but can be ubiquitously upregulated in diverse tissues at sites of inflammation, an effect that is paramount in the progression of various pathologies.6 The seemingly simplistic distinction between beneficial COX-1 and deleterious COX-2 led to the development of selective COX-2 inhibitors. Although these drugs successfully suppressed inflammation while minimizing the gastrointestinal complications of nonselective COX inhibitors,7 cardiovascular complications attributed to disruption of the tightly regulated equilibrium of prostaglandin (PG) production in the blood vessel is less than ideal.
COX enzymes produce PGs that both prevent and promote vascular diseases. Under physiological conditions, COX catalysis relies on the COX and peroxidase functionalities of this enzyme. The COX domain catalyzes the conversion of arachidonic acid (AA) to PGG2, and the peroxidase domain catalyzes the reduction of PGG2 to an unstable endoperoxide, PGH2. Via the action of specific downstream synthases, PGH2 is converted to species including thromboxane A2 (TxA2), PGE2, and prostacyclin (PGI2). Platelet-derived TxA2 is a potent platelet activator and vasoconstrictor,8 whereas PGE2 is a proinflammatory molecule associated with atherosclerotic plaque destabilization.9 Conversely, PGI2, the major product of vascular endothelial cells, is a powerful vasodilator and inhibitor of platelet activation and adhesion10 (Figure 2). The benefit of low-dose aspirin in reducing cardiovascular disease results from selective acetylation of COX-1 and blockade of TxA2 formation by platelets while retaining endothelial PGI2 production.11 COX-2 provides a crucial source of PGI2 in humans; thus, a reduction in PGI2 production, coupled with unchecked COX-1–dependent platelet-derived TxA2, was inferred to mediate adverse cardiovascular events.12 If this is indeed the case, would a selective COX-2 inhibitor combined with a platelet-selective low dose of aspirin provide protection against these adverse effects?
|
Current evidence indicates that cardiovascular risk is not only associated with selective COX-2 inhibitors but also with long-term treatment with traditional NSAIDs.13 Endothelial COX-1 from normal vessels may be more readily inhibited by NSAIDs than platelet COX-1, preventing endothelial PGI2 formation but not platelet-derived TxA2.14 It may be that the apparent selectivity of a given COX inhibitor is determined by a target cell’s peroxide content and arachidonate availability, rather than selectivity for a particular isoform.14
Because PGI2 is vasoprotective, it is not surprising that COX-2 induction can generate compensatory PGI2 at sites of vascular injury. Indeed, COX-2 is highly expressed in atherosclerotic lesions in animal models and humans.15,16 However, an increase in COX-2 expression also results in increased production of proinflammatory PGs, such as PGE2, which stimulate matrix metalloproteinase expression and contribute to atherosclerotic plaque rupture.17 Accordingly, selective COX-2 inhibition in low-density lipoprotein receptor–deficient mice was found to diminish aortic atherogenesis.18 Furthermore, a naturally occurring polymorphism in the COX-2 promoter that results in decreased COX-2 expression has been associated with a reduced incidence of cardiovascular events in humans.19 Therefore, a global reduction in COX-2–derived PGs at sites of injury may have limited benefit, and the quest for a more focused interference, eg, selective targeting of individual PG receptor subtypes, may be more desirable.
Despite sharing a common agonist, each of the 4 PGE2 receptors (EP1 to EP4) use multiple signaling pathways to elicit diverse and opposing physiological effects in the cardiovascular system. For example, PGE2 receptor subtypes differentially regulate metalloproteinases and play a pivotal role in the regulation of plaque stability. Genetic silencing of EP4 expression or administration of a selective EP4 antagonist (ONO-AE3-208) was shown to significantly reduce COX-2–dependent metalloproteinase expression in macrophages.20 On the other hand, studies with EP3-deficient mice demonstrate that PGE2 facilitates arterial thrombosis and mechanical plaque rupture via EP3 activation.21 In addition to influences on plaque stability, PGE2 has been shown to play differential roles in the regulation of vascular smooth muscle tone and blood pressure.22 For example, EP1 and EP3 are associated with vasoconstriction, whereas EP2 and EP4 promote vasodilation22 (Figure 1). Recent findings have shown that administration of the EP1 receptor antagonist SC51322, or selective genetic disruption of the EP1 receptor, reduces blood pressure and is, thus, a potential target for the treatment of hypertension.23
|
The diverse nature of PGE2-mediated effects highlights the need for selective pharmacological targeting of specific inflammatory PG signaling pathways. Structure-function studies of enzymes and receptors relevant to PG signaling pathways, coupled with the availability of high-throughput screening methods, should drive the development of novel compounds that selectively target specific PGs with diminished adverse effects, relative to more broadly acting COX inhibitors (Figure 1).
Redressing the Balance of COX Products With Alternative Substrates
The preferred substrate for COX is AA (an omega-6 fatty acid), although eicosapentaenoic acid (EPA; an omega-3 fatty acid enriched in dietary fish oils) also serves as a substrate. Of note, AA-derived PGs contribute to a stronger inflammatory response than their EPA-derived counterparts. As such, omega-6 fatty acid–rich Western diets are believed to contribute to the genesis of vasoinflammatory disorders, including atherosclerosis and diabetes. AA and EPA can also undergo nonenzymatic oxidation in vivo to generate vasoactive hydroperoxides, epoxides, and isoprostanes.24 In fact, quantification of urinary isoprostane has served as a marker of oxidative stress and lipid peroxidation in association with various inflammatory conditions.25 Interestingly, dietary supplementation of EPA in rodents increased noninflammatory EPA-derived isoprostanes while reducing proinflammatory AA-derived isoprostanes.26 EPA-derived mediators may also have decreased inflammatory potential, because EPA-derived PGE3 induced COX-2 to a significantly lesser extent than AA-derived PGE2.27 Furthermore, rabbits receiving omega-3 fatty acids experienced a significant reduction in infarct size resulting from ischemia-reperfusion injury.28 Together, these studies indicate that alternative COX substrates yield different PG products, and this knowledge may be exploitable for future diet-based suppression of inflammation.
The differential metabolism of EPA and AA by COX enzymes can be explained biochemically by the activating peroxide concentration requirement for the enzyme.29 Although COX-2 readily metabolizes EPA, COX-1 does so poorly. Notwithstanding, in hydroperoxide-rich cells such as platelets, EPA is efficiently metabolized by COX-1 to TxA3, an inactive thromboxane receptor ligand.30 Therefore, increased EPA availability relative to AA can result in decreased formation of active COX-1–derived thromboxanes in platelets; conceivably, dietary EPA can provide an alternative to aspirin for decreasing thrombogenesis while avoiding gastrointestinal afflictions.
Investigations of targets that involve non-COX pathways of AA metabolism are also of interest. In fact, other AA-metabolizing enzymes, such as LOXs and cytochrome P450s, each producing lipid mediators with a variety of biological consequences in inflammatory diseases, may indirectly modulate COX and PG synthesis. Administration of NSAIDs was found to shift AA flow from COXs to the cytochrome P450 pathway resulting in increased accumulation of anti-inflammatory epoxides.31 Alternatively, 12-LOX metabolites, such as 12-hydroxyeicosatetraenoic acid, that are inflammatory can exert a regulatory role on COX-2 gene transcription and PG production.32 Interestingly, exogenous administration of anti-inflammatory epoxides or inhibition of soluble epoxide hydrolase, the enzyme that hydrolyzes anti-inflammatory epoxides to the corresponding diols, is anti-inflammatory in a variety of disease models.31,33 Therefore, combination therapy with soluble epoxide hydrolase inhibitors and NSAIDs (at a reduced dose) promises the benefit of alleviating pain and inflammation while simultaneously reducing undesired adverse effects associated with NSAIDs.31
|
Targeting Oxidative Stress and Vascular Dysfunction |
|---|
|
TopIntroductionThe Prostaglandin Biosynthesis...Targeting Oxidative Stress and...Future Therapeutic Potentials...References |
|---|
Endothelial Dysfunction
Endothelial dysfunction is characterized by impaired endothelium-dependent relaxation in association with dysregulation of cell signaling pathways, alterations in prothrombotic/antithrombotic factor activities and increased cell permeability. Importantly, many of these phenotypic changes have been linked to diminished bioavailability of endothelium-derived ·NO. Endothelial NO synthase (NOS; eNOS) provides the essential source of vascular ·NO for regulating blood flow, oxygen delivery, and vascular tone, although inducible NOS (iNOS) and neuronal NOS may contribute under certain conditions.34 In accord with the fundamental importance of ·NO in maintaining vascular homeostasis, endothelial dysfunction has been implicated in the pathogenesis of chronic vascular disorders including diabetes, hypertension, and atherosclerosis.35,36
Under normal physiological conditions, cellular respiration and metabolism produce low levels of reactive oxygen species (ROS), including superoxide anion (O2·–), hydroxyl radical, and peroxyl radicals. Key sources of vascular O2·– include the mitochondrial electron transport chain, LOXs, COXs, xanthine oxidases, and reduced nicotinamide-adenine dinucleotide phosphate oxidases.37 Cells are equipped with antioxidant defense mechanisms that function to suppress cellular ROS levels. However, inflammatory cells can generate bursts of oxidants that defend the host against invading organisms and overwhelm antioxidant defense systems leading to pathophysiological conditions associated with vascular ·NO insufficiency.38 Prevention of ROS-dependent losses in ·NO bioavailability has emerged as a therapeutic goal for the management of many cardiovascular disorders.
eNOS Recoupling Therapy
Increased production of ROS can disrupt the tightly regulated eNOS catalytic machinery in endothelial cells, leading to preferential O2·– generation in lieu of ·NO, a phenomenon termed "eNOS uncoupling."3 Production of ·NO in the setting of O2·– excess favors the formation of peroxynitrite (ONOO–), a cytotoxic species that can profoundly override protection afforded by superoxide dismutases3 and inhibit glutathione peroxidase.39 ROS can also deplete antioxidants like vitamin C and glutathione that serve to maintain the cellular redox status.3 Although antioxidant deficiencies seem to contribute to the impairment of vascular function,40 antioxidant therapies are generally ineffective in limiting the pathogenesis of these conditions. Explanations for this paradox have focused on the complexity of oxidative reactions and the differential subcellular localization associated with the synthesis and accessibility of pro-oxidant and antioxidant species.41
Recently, more targeted approaches have been used to enhance NOS coupling efficiency, such as treatment with tetrahydrobiopterin (BH4), an essential cofactor of NOS.42,43 Treatment with BH4 has been shown to acutely reverse impaired endothelium-dependent vasodilatation associated with hypercholesterolemia and diabetes.44,45 Similarly, gene therapy to increase expression of GTP-cyclohydrolase I, the rate-limiting enzyme in BH4 synthesis, can reverse endothelial dysfunction and reduce atherosclerotic lesion formation in atherogenic mice that overexpress eNOS. Paradoxically, an increase in eNOS expression without a commensurate increase in BH4 cofactor availability enhances oxidative stress.41 In a recent study, atherosclerotic patients receiving a low dose of folic acid, which enhances BH4 bioavailability, were found to have improved eNOS activity and attenuated vascular dysfunction. The vascular benefits of folate were highly dependent on vascular levels of the metabolite 5- methyltetrahydrofolate,46 which efficiently scavenges ONOO– and protects BH4 from oxidative inactivation.47
·NO bioavailability can potentially be enhanced by increasing L-arginine availability. Although a number of small case studies have suggested a beneficial effect of arginine supplementation in animals and humans with atherosclerosis,48,49 other studies have challenged these findings.50 One potential avenue of therapy involves modulation of arginase. Enhanced expression and activation of arginase, the enzyme responsible for the conversion of arginine to L-ornithine, has been implicated in endothelial dysfunction in animal models of hypertension and atherosclerosis.51,52 Accordingly, if arginase inhibition could be achieved while preserving the urea cycle, some patients may benefit.
Thus, in the process of evaluating new approaches for the treatment of endothelial dysfunction, a newfound appreciation for uncoupled eNOS as a significant therapeutic target has emerged. We anticipate positive outcomes of eNOS recoupling therapies from definitive clinical trials for conditions associated with endothelial dysfunction.
Inducible NOS: Pathological or Beneficial?
iNOS is upregulated in cells exposed to a variety of proinflammatory insults. Excessive production of iNOS-derived ·NO can serve as a compensatory mechanism to replenish anti-inflammatory ·NO in the face of eNOS uncoupling or as a pathological mechanism promoting inflammation via the formation of higher oxides of nitrogen (NOx). For example, the simultaneous overproduction of ·NO and O2·– and reaction at diffusion-controlled rates to form ONOO– can result in profound oxidation of biological molecules at sites of inflammation. Because the rate constant for superoxide dismutase is lower than that for the reaction of ·NO and O2·–, ONOO– formation can be the major fate of O2·–.53 Results predominantly indicate that low levels of ·NO produced by eNOS are beneficial, whereas continuous production of ·NO by iNOS is cytostatic. This paradigm seems to extend to vascular inflammatory conditions, such as atherogenesis54 and immunoactivated vascular smooth muscle cells.55
Interestingly, EPA, known for its cardiovascular benefits (discussed earlier), exerts its anti-inflammatory beneficial actions, in part, by enhanced ·NO synthesis. Administration of EPA stimulated ·NO production from eNOS and improved cardiac function in diabetic rats.56 EPA was also shown to promote the synthesis of ·NO and reduce myocardial infarct size in rabbit hearts57 and to significantly suppress iNOS gene expression in hypertrophied cardiomyocytes.58 Possible mechanisms of iNOS downregulation by EPA may include activation of calcium channel–mediated signaling pathways57 and peroxisome proliferator-activated receptor-retinoid X receptor pathways that suppress nuclear factor 
B–induced iNOS gene expression.59
Inflammatory stimuli trigger the expression of COX-2, iNOS, and nitration of proteins that colocalize in atherosclerotic lesions, accumulating mainly in macrophages.60 Recently, a direct physical interaction of iNOS and COX-2 was demonstrated in macrophages, engendering specific nitrosylation of COX-2 on a defined cysteine residue that results in enhanced catalytic activity.61 Recognition of the direct interaction between iNOS and COX-2 has stimulated interest in pharmacological manipulations of iNOS that may limit inflammatory PG synthesis as an alternative to selective COX-2 inhibitors. Mounting evidence of COX nitration provides another example of how ·NO-dependent modifications can alter the COX structure and function, reaffirming the mutually interactive nature of the NOS/COX systems.
Is Posttranslational Inhibition of COX by NOx Biologically Relevant?
The complex nature of ·NO chemistry, its related modifications of biomolecules, and attendant cellular responses, create a challenge for defining the role of ·NO in physiological and pathophysiological processes. This complexity involves the following: (1) identification of the relevant ·NO-derived species (NOx), eg, ·NO itself, nitrogen dioxide, ONOO–, and nitrosoperoxocarbonate3; (2) determination of the identity of the protein(s) subject to modification by NOx; (3) identification of the nature and sites of these modifications; and (4) elucidation of the consequences of modification for protein functions. The study of NOx-dependent modifications of COX enzymes have resulted in inconsistent reports of activation62,63 and inhibition.64–66 These studies have described a variety of COX modifications, including heme oxidation, tyrosine (Tyr) nitration, and cysteine nitrosylation, all of which likely underlie the divergent actions of NOx species on COX enzyme activities.
NOx-initiated modifications of COX can elicit 2 alternative outcomes: activation of COX (eg, by heme oxidation and cysteine S-nitrosylation), favoring prostacyclin (PGI2) production and maintenance of vessel homeostasis, and inhibition of COX (eg, by Tyr nitration) suppressing PGI2 production, thus favoring TxA2 synthesis and vascular disease. Although the functional changes in COX that are elicited by these alternative NOx-induced modifications may be clear, conditions under which a particular reaction predominates remains undefined, and the extent to which these modifications determine COX activity in vivo remains to be established.67
COX Nitration: A Pathological Modification or Nature’s "Aspirin"?
Essential criteria must be realized for a particular posttranslational protein modification to be considered physiologically relevant. Is it molecularly selective, reversible, and/or extensive? Does it significantly alter protein functions?
S-Nitrosylation of proteins, the covalent addition of ·NO to particular cysteine residues, is now recognized as a physiologically important posttranslational modification for the control of numerous proteins in the cardiovascular system.68,69 However, Tyr nitration of proteins has not garnered the same attention. Indeed, Tyr nitration is often considered to be a toxic and irreversible modification that occurs in the setting of extreme oxidative stress, commonly resulting in a loss of protein function, disruption of cell signaling cascades, and/or accelerated protein degradation.70 However, intriguing studies describe an organ-specific and regulatory enzymatic activity that can remove protein Tyr nitration via the action of an inferred class of "denitrase" enzymes.71–73 Thus, it is possible that nitration of Tyr residues plays a moment-to-moment regulatory role in vasoinflammatory processes and, potentially, their resolution (Figure 2).
Recent reports have described a pivotal role for protein transition metal ions in selectively targeting nitration by ONOO– to specific Tyr residues. This phenomenon has been documented for ferric hemoglobin, cytochrome P450, prostacyclin synthase, and COX-116,66,74–76 and occurs by a pathway that allows for the decay of ONOO– to an efficient nitrating species, nitrogen dioxide, formed in close proximity to the targeted Tyr. For prostacyclin synthase, an enzyme downstream of COX, a heme-iron selectively targets nitration to Tyr430, resulting in a loss of catalytic activity.75 For COX-1, nitration is selectively targeted to Tyr385 resulting in inactivation; notably, whereas COX-1 nitration occurs in the absence of heme, this is not on Tyr385 and has no detectable impact on COX function.16,66 These studies highlight the importance of the metal-porphyrin group in hemoproteins for selective targeting of Tyr nitration by ONOO–.66,75 Importantly, nitrated COX-1 has been identified in mouse and human atherosclerotic lesional tissue.16,65 Because ONOO– is a short-lived species that acts locally, selective nitration of COX-1 by ONOO– can be viewed as nature’s aspirin, providing a mechanism for limiting synthesis of inflammatory PGs at focal sites of inflammation. Much like the use of isoform-selective COX inhibitors, selective targeting of nitration to sites of inflammation may serve to spatially restrict PG synthesis and promote the resolution of inflammation (Figure 2).
Currently, it is difficult to estimate the physiological/pathophysiological importance of COX inhibition by nitration. However, given that PGs can have opposing actions, it is reasonable to assume that selective and organ-specific COX nitration can be beneficial at sites where PGs are disease promoting. Alternatively, COX denitration may assist in resolving inflammation in organs where the loss of PGs contributes to disease progression.
|
Future Therapeutic Potentials for Hybrid COX Inhibitors |
|---|
|
TopIntroductionThe Prostaglandin Biosynthesis...Targeting Oxidative Stress and...Future Therapeutic Potentials...References |
|---|
Appreciation of the fact that the heme peroxidase site in COX can catalyze chemical reactions independent of AA metabolism has triggered a great deal of interest in the development of agents with the dual capacity to inhibit both the COX and peroxidase reactions.77 In addition to heme oxidation by ROS and NOx species, the COX peroxidase site can oxidize electron donor compounds such as polycyclic aromatic hydrocarbons from cigarette smoke. The latter reaction can lead to polar, highly reactive, and strongly mutagenic intermediates that attack DNA and proteins.78 Such intermediates can exacerbate inflammation and alter PG biosynthesis by inducing COX-2 expression at sites of vascular injury,79 activating nuclear factor
B and activator protein-180 and suppressing prostacyclin synthase gene expression.81 Dual inhibitors of peroxidase and COX activities would dampen a currently untargeted COX function (peroxidase), such new drugs that await evaluation. ·NO-donating NSAIDs (COX-inhibiting ·NO donators) are another new generation of hybrid COX inhibitors that are being evaluated in the clinic. These agents are defined by the covalent addition of ·NO to oxygen in NSAIDs and benefit from the combined anti-inflammatory and antihypertensive actions of ·NO donation and COX inhibition along with gastrointestinal preservation afforded by ·NO82 (Figure 1). Clinical studies in osteoarthritic patients with one such agent, nitronaproxen, were favorable, particularly in hypertensive patients where a potent anti-inflammatory response accompanied treatment.83 Development of COX-inhibiting ·NO donators for a wide variety of NSAIDs,84 including aspirin (NCX 4016; ·NO-donating aspirin) for potential therapy of cardiovascular diseases, is currently underway.85 Thus, optimal anti-inflammatory therapy with reduced risk may start with what we know is effective, ie, conventional COX-inhibiting NSAIDs, fine tuned for ·NO delivery.
Perspectives
It is well recognized that the protection against atherosclerosis resides in the endothelium. However, more complete molecular details for how the endothelium exerts its vasoprotective action are needed, as is a clarification of the interactions of vascular mediators and oxidant stress that promote vascular damage. Ongoing investigations of the cross-talk between the COX and the ·NO pathway have provided new possibilities for the regulation of PG production. As the complex chemistry between NOx and its protein targets is being increasingly defined, there is a growing appreciation that outcomes of this chemistry are dependent on the intracellular milieu, which will impact on disease progression. Harnessing knowledge that emerges from studies that define biologically relevant interactions of ·NO and COX is expected to provide novel insights for the therapy of vasoinflammatory conditions. Currently, the development of new agents that target specific proinflammatory PGs, rather than COX itself, and the development of hybrid COX inhibitors that offer safer anti-inflammatory actions, represent promising new directions for pharmacotherapy of chronic cardiovascular disease.
|
Acknowledgments |
|---|
Sources of Funding
This work was supported by National Institutes of Health grants to D.P.H. (HL46403, HL072942, and T-32 HL07423) and to S.S.G. (HL46403 and HL80702); by a Philip Morris USA, Inc, and Philip Morris International grant to R.K.U.; and by the Abercombie Foundation.
Disclosures
None.
Received August 17, 2007; first decision September 6, 2007; accepted October 18, 2007.
|
References |
|---|
|
TopIntroductionThe Prostaglandin Biosynthesis...Targeting Oxidative Stress and...Future Therapeutic Potentials...References |
|---|
1. Hansson GK. Mechanisms of disease - inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685–1695.
2. Williams MD, Nadler JL. Inflammatory mechanisms of diabetic complications. Curr Diab Rep. 2007; 7: 242–248.[CrossRef][Medline] [Order article via Infotrieve]
3. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87: 315–424.
4. Miller SB. Prostaglandins in health and disease: an overview. Semin Arthritis Rheum. 2006; 36: 37–49.[CrossRef][Medline] [Order article via Infotrieve]
5. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, Weaver A, Grp VS. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343: 1520–1528.
6. Hla T, Ristimaki A, Appleby S, Barriocanal JG. Cyclooxygenase gene expression in inflammation and angiogenesis. Ann N Y Acad Sci. 1993; 696: 197–204.[Medline] [Order article via Infotrieve]
7. Futaki N, Yoshikawa K, Hamasaka Y, Arai I, Higuchi S, Iizuka H, Otomo S. Ns-398, a novel nonsteroidal antiinflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions. Gen Pharmacol. 1993; 24: 105–110.[Medline] [Order article via Infotrieve]
8. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973–979.
9. Cipollone F, Fazia M, Iezzi A, Ciabattoni G, Pini B, Cuccurullo C, Ucchino S, Spigonardo F, De Luca M, Prontera C, Chiarelli F, Cuccurullo F, Mezzetti A. Balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans. Arterioscler Thromb Vasc Biol. 2004; 24: 1259–1265.
10. Moncada S. Prostacyclin and arterial wall biology. Arterioscler Thromb Vasc Biol. 1982; 2: 193–207.
11. Fitzgerald GA, Oates J, Hawiger J, Maas RL, Roberts LJ, Lawson JA, Brash AR. Endogenous biosynthesis of prostacyclin and thromboxane and platelet-function during chronic administration of aspirin in man. J Clin Invest. 1983; 71: 676–688.[Medline] [Order article via Infotrieve]
12. Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, FitzGerald GA. Role of prostacyclin in the cardiovascular response to thromboxane A(2). Science. 2002; 296: 539–541.
13. Bishop-Bailey D, Mitchell JA, Warner TD. COX-2 in cardiovascular disease. Arterioscler Thromb Vasc Biol. 2006; 26: 956–958.
14. Mitchell JA, Lucas R, Vojnovic I, Hasan K, Pepper JR, Warner TD. Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events. FASEB J. 2006; 20: 2468–2475.
15. Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol. 1999; 155: 1281–1291.
16. Deeb RS, Shen H, Gamss C, Gavrilova T, Summers BD, Kraemer R, Hao G, Gross SS, Laine M, Maeda N, Hajjar DP, Upmacis RK. Inducible nitric oxide synthase mediates prostaglandin H-2 synthase nitration and suppresses eicosanoid production. Am J Pathol. 2006; 168: 349–362.
17. Cipollone F, Prontera C, Pini B, Marini M, Fazia M, De Cesare D, Iezzi A, Ucchino S, Boccoli G, Saba V, Chiarelli F, Cuccurullo F, Mezzetti A. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E-2-dependent plaque instability. Circulation. 2001; 104: 921–927.
18. Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002; 105: 1816–1823.
19. Cipollone F, Toniato E, Martinotti S, Fazia M, Iezzi A, Cuccurullo C, Pini B, Ursi S, Vitullo G, Averna M, Arca M, Montali A, Campagna F, Ucchino S, Spigonardo F, Taddei S, Virdis A, Ciabattoni G, Notarbartolo A, Cuccurullo F, Mezzetti A, Grp IS. A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA. 2004; 291: 2221–2228.
20. Pavlovic S, Du B, Sakamoto K, Khan KMF, Natarajan C, Breyer RM, Dannenberg AJ, Falcone DJ. Targeting prostaglandin E-2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages. J Biol Chem. 2006; 281: 3321–3328.
21. Gross S, Tilly P, Hentsch D, Vonesch JL, Fabre JE. Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors. J Exp Med. 2007; 204: 311–320.
22. Breyer MD, Breyer RM. Prostaglandin E receptors and the kidney. Am J Physiol-Renal Physiol. 2000; 279: F12–F23.
23. Guan Y, Zhang Y, Wu J, Qi Z, Yang G, Dou D, Gao Y, Chen L, Zhang X, Davis LS, Wei M, Fan X, Carmosino M, Hao C, Imig JD, Breyer RM, Breyer MD. Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting. J Clin Invest. 2007; 117: 2496–2505.[CrossRef][Medline] [Order article via Infotrieve]
24. Porter Na, Caldwell SE, Mills KA. Mechanisms of free-radical oxidation of unsaturated lipids. Lipids. 1995; 30: 277–290.[Medline] [Order article via Infotrieve]
25. Morrow JD. The isoprostanes: their quantification as an index of oxidant stress status in vivo. Drug Metab Rev. 2000; 32: 377–385.[CrossRef][Medline] [Order article via Infotrieve]
26. Gao L, Yin HY, Milne GL, Porter NA, Morrow JD. Formation of F-ring isoprostane-like compounds (F-3-isoprostanes) in vivo from eicosapentaenoic acid. J Biol Chem. 2006; 281: 14092–14099.
27. Bagga D, Wang L, Farias-Eisner R, Glaspy JA, Reddy ST. Differential effects of prostaglandin derived from omega-6 and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci U S A. 2003; 100: 1751–1756.
28. McGuinness J, Neilan TG, Sharkasi A, Bouchier-Hayes D, Redmond JM. Myocardial protection using an omega-3 fatty acid infusion: Quantification and mechanism of action. J Thorac Cardiovasc Surg. 2006; 132: U72–U62.[CrossRef]
29. Kulmacz RJ, Pendleton RB, Lands WE. Interaction between peroxidase and cyclooxygenase activities in prostaglandin-endoperoxide synthase. Interpretation of reaction kinetics. J Biol Chem. 1994; 269: 5527–5536.
30. Morita I, Takahashi R, Saito Y, Murota S. Stimulation of eicosapentaenoic acid metabolism in washed human-platelets by 12-hydroperoxyeicosatetraenoic acid. J Biol Chem. 1983; 258: 197–199.
31. Inceoglu B, Schmelzer KR, Morisseau C, Jinks SL, Hammock BD. Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs). Prostaglandins Other Lipid Mediat. 2007; 82: 42–49.[CrossRef][Medline] [Order article via Infotrieve]
32. Han X, Chen SY, Sun YJ, Nadler JL, Bleich D. Induction of cyclooxygenase-2 gene in pancreatic beta-cells by 12-lipoxygenase pathway product 12-hydroxyeicosatetraenoic acid. Mol Endocrinol. 2002; 16: 2145–2154.[Abstract]
33. Ai D, Fu Y, Guo DL, Tanaka H, Wang NP, Tang CS, Hammock BD, Shyy JYJ, Zhu Y. Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. Proc Natl Acad Sci U S A. 2007; 104: 9018–9023.
34. Martasek P, Liu Q, Liu JW, Roman LJ, Gross SS, Sessa WC, Masters BSS. Characterization of bovine endothelial nitric oxide synthase expressed in E-coli. Biochem Biophys Res Commun. 1996; 219: 359–365.[CrossRef][Medline] [Order article via Infotrieve]
35. Han SH, Quon MJ, Koh KK. Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction. Curr Opin Lipidol. 2007; 18: 58–65.[Medline] [Order article via Infotrieve]
36. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
37. Zou MH. Peroxynitrite and protein tyrosine nitration of prostacyclin synthase. Prostaglandins Other Lipid Mediat. 2007; 82: 119–127.[CrossRef][Medline] [Order article via Infotrieve]
38. Sies H. Oxidative stress - from basic research to clinical-application. Am J Med. 1991; 91: S31–S38.[Medline] [Order article via Infotrieve]
39. Sies H, Sharov VS, Klotz LO, Briviba K. Glutathione peroxidase protects against peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase. J Biol Chem. 1997; 272: 27812–27817.
40. d’Uscio LV, Milstien S, Richardson D, Smith L, Katusic ZS. Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ Res. 2003; 92: 88–95.
41. Takaya T, Hirata K-I, Yamashita T, Shinohara M, Sasaki N, Inoue N, Yada T, Goto M, Fukatsu A, Hayashi T, Alp NJ, Cahnnon KM, Yokoyama M, Kawashima S. A specific role for eNOS-derived reactive oxygen species in atherosclerosis progression. Arterioscler Thromb Vasc Biol. 2007; 27: 1–7.
42. Hevel JM, Marletta MA. Macrophage nitric-oxide synthase - relationship between enzyme-bound tetrahydrobiopterin and synthase activity. Biochemistry. 1992; 31: 7160–7165.[CrossRef][Medline] [Order article via Infotrieve]
43. Gross SS, Jones CL, Hattori Y, Raman CS. Tetrahydrobiopterin: an essential cofactor of nitric oxide synthase with an elusive role. In: Ignarro LJ, ed. Nitric Oxide: Biology and Pathobiology. San Diego CA: Academic Press; 2000: 167–185.
44. Stroes E, Kastelein J, Cosentino F, Erkelens W, Wever R, Koomans H, Luscher T, Rabelink T. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest. 1997; 99: 41–46.[Medline] [Order article via Infotrieve]
45. Pieper GM. Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. J Cardiovasc Pharmacol. 1997; 29: 8–15.[CrossRef][Medline] [Order article via Infotrieve]
46. Shirodaria C, Antoniades C, Lee J, Jackson CE, Robson MD, Francis JM, Moat SJ, Ratnatunga C, Pillai R, Refsum H, Neubauer S, Channon KM. Global improvement of vascular function and redox state with low-dose folic acid—implications for folate therapy in patients with coronary artery disease. Circulation. 2007; 115: 2262–2270.
47. Antoniades C, Shirodaria C, Warrick N, Cai SJ, de Bono J, Lee J, Leeson P, Neubauer S, Ratnatunga C, Pillai R, Refsum H, Channon KM. 5-Methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels - effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation. 2006; 114: 1193–1201.
48. Drexler H, Zeiher aM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet. 1991; 338: 1546–1550.[CrossRef][Medline] [Order article via Infotrieve]
49. Cooke JP, Singer AH, Tsao P, Zera P, Rowan RA, Billingham ME. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992; 90: 1168–1172.[Medline] [Order article via Infotrieve]
50. Wennmalm A, Edlund A, Granstrom EF, Wiklund O. Acute supplementation with the nitric oxide precursor L-arginine does not improve cardiovascular performance in patients with hypercholesterolemia. Atherosclerosis. 1995; 118: 223–231.[CrossRef][Medline] [Order article via Infotrieve]
51. Ming XF, Barandier C, Viswambharan H, Kwak BR, Mach F, Mazzolai L, Hayoz D, Ruffieux J, Rusconi S, Montani JP, Yang ZH. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway—implications for atherosclerotic endothelial dysfunction. Circulation. 2004; 110: 3708–3714.
52. Johnson FK, Johnson RA, Peyton KJ, Durante W. Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension. Am J Physiol-Regul Integr Comp Physiol. 2005; 288: R1057–R1062.
53. Beckman JS, Crow JP. Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem Soc Trans. 1993; 21: 330–334.[Medline] [Order article via Infotrieve]
54. Ikeda U, Maeda Y, Shimada K. Inducible nitric oxide synthase and atherosclerosis. Clin Cardiol. 1998; 21: 473–476.[Medline] [Order article via Infotrieve]
55. Hattori Y, Kasai K, Gross SS. NO suppresses while peroxynitrite sustains NF-kappa B: a paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO. Cardiovasc Res. 2004; 63: 31–40.
56. Nishimura M, Nanbu A, Komori T, Ohtsuka K, Takahashi H, Yoshimura M. Eicosapentaenoic acid stimulates nitric oxide production and decreases cardiac noradrenaline in diabetic rats. Clin Exp Pharmacol Physiol. 2000; 27: 618–624.[CrossRef][Medline] [Order article via Infotrieve]
57. Ogita H, Node K, Asanuma H, Sanada S, Takashima S, Minamino T, Soma M, Kim J, Hori M, Kitakaze F. Eicosapentaenoic acid reduces myocardial injury induced by ischemia and reperfusion in rabbit hearts. J Cardiovasc Pharmacol. 2003; 41: 964–969.[CrossRef][Medline] [Order article via Infotrieve]
58. Shimojo N, Jesmin S, Zaedi S, Soma M, Kobayashi T, Maeda S, Yamaguchi I, Goto K, Miyauchi T. EPA effect on NOS gene expression and on NO level in endothelin-1-induced hypertrophied cardiomyocytes. Exp Biol Med. 2006; 231: 913–918.
59. Selvaraj RK, Klasing KC. Lutein and eicosapentaenoic acid interact to modify iNOS mRNA levels through the PPAR gamma/RXR pathway in chickens and HD11 cell lines. J Nutr. 2006; 136: 1610–1616.
60. Baker CS, Hall RJ, Evans TJ, Pomerance A, Maclouf J, Creminon C, Yacoub MH, Polak JM. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc Biol. 1999; 19: 646–655.
61. Kim SF, Huri DA, Snyder SH. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005; 310: 1966–1970.
62. Landino LM, Crews BC, Timmons MD, Morrow JD, Marnett LJ. Peroxynitrite, the coupling product of nitric oxide and superoxide, activates prostaglandin biosynthesis. Proc Natl Acad Sci U S A. 1996; 93: 15069–15074.
63. Upmacis RK, Deeb RS, Hajjar DP. Regulation of prostaglandin H2 synthase activity by nitrogen oxides. Biochemistry. 1999; 38: 12505–12513.[CrossRef][Medline] [Order article via Infotrieve]
64. Kanner J, Harel S, Granit R. Nitric oxide, an inhibitor of lipid oxidation by lipoxygenase, cyclooxygenase and hemoglobin. Lipids. 1992; 27: 46–49.[Medline] [Order article via Infotrieve]
65. Deeb RS, Resnick MJ, Mittar D, McCaffrey T, Hajjar DP, Upmacis RK. Tyrosine nitration in prostaglandin H2 synthase. J Lipid Res. 2002; 43: 1718–1726.
66. Deeb RS, Hao G, Gross SS, Laine M, Qiu JH, Resnick B, Barbar EJ, Hajjar DP, Upmacis RK. Heme catalyzes tyrosine 385 nitration and inactivation of prostaglandin H-2 synthase-1 by peroxynitrite. J Lipid Res. 2006; 47: 898–911.
67. Upmacis RK, Deeb RS, Hajjar DP. Oxidative alterations of cyclooxygenase during atherogenesis. Prostaglandins Other Lipid Mediat. 2006; 80: 1–14.[CrossRef][Medline] [Order article via Infotrieve]
68. Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS. Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol. 2005; 6: 150–166.[CrossRef][Medline] [Order article via Infotrieve]
69. Derakhshan B, Hao G, Gross SS. Balancing reactivity against selectivity: the evolution of protein S-nitrosylation as an effector of cell signaling by nitric oxide. Cardiovasc Res. 2007; 75: 210–219.
70. Grune T, Blasig IE, Sitte N, Roloff B, Haseloff R, Davies KJA. Peroxynitrite increases the degradation of aconitase and other cellular proteins by proteasome. J Biol Chem. 1998; 273: 10857–10862.
71. Kamisaki Y, Wada K, Bian K, Balabanli B, Davis K, Martin E, Behbod F, Lee YC, Murad F. An activity in rat tissues that modifies nitrotyrosine-containing proteins. Proc Natl Acad Sci U S A. 1998; 95: 11584–11589.
72. Koeck T, Fu XM, Hazen SL, Crabb JW, Stuehr DJ, Aulak KS. Rapid and selective oxygen-regulated protein tyrosine denitration and nitration in mitochondria. J Biol Chem. 2004; 279: 27257–27262.
73. Gorg B, Qvartskhava N, Voss P, Grune T, Haussinger D, Schliess F. Reversible inhibition of mammalian glutamine synthetase by tyrosine nitration. FEBS Lett. 2007; 581: 84–90.[CrossRef][Medline] [Order article via Infotrieve]
74. Pietraforte D, Salzano AM, Scorza G, Marino G, Minnetti M. Mechanism of peroxynitrite interaction with ferric hemoglobin and identification of nitrated tyrosine residues. CO2 inhibits heme-catalyzed scavenging and isomerization. Biochemistry. 2001; 40: 15300–15309.[CrossRef][Medline] [Order article via Infotrieve]
75. Schmidt P, Youhnovski N, Daiber A, Balan A, Arsic M, Bachschmid M, Przybylski M, Ullrich V. Specific nitration at tyrosine 430 revealed by high resolution mass spectrometry as basis for redox regulation of bovine prostacyclin synthase. J Biol Chem. 2003; 278: 12813–12819.
76. Daiber A, Bachschmid M, Beckman JS, Munzel T, Ullrich V. The impact of metal catalysis on protein tyrosine nitration by peroxynitrite. Biochem Biophys Res Commun. 2004; 317: 873–881.[CrossRef][Medline] [Order article via Infotrieve]
77. Loll PJ, Sharkey CT, O’Connor SJ, Dooley CM, O’Brien E, Devocelle M, Nolan KB, Selinsky BS, Fitzgerald DJ. O-Acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions. Mol Pharmacol. 2001; 60: 1407–1413.
78. Marnett LJ, Reed Ga, Dennison DJ. Prostaglandin synthetase dependent activation of 7,8-dihydro-7,8-dihydroxy-benzo(a)pyrene to mutagenic derivatives. Biochem Biophys Res Commun. 1978; 82: 210–216.[CrossRef][Medline] [Order article via Infotrieve]
79. Kelley DJ, Mestre JR, Subbaramaiah K, Sacks PG, Schantz SP, Tanabe T, Inoue H, Ramonetti JT, Dannenberg AJ. Benzo[a]pyrene up-regulates cyclooxygenase-2 gene expression in oral epithelial cells. Carcinogenesis. 1997; 18: 795–799.
80. Janknecht R, Cahill MA, Nordheim A. Signal integration at the C-Fos promoter. Carcinogenesis. 1995; 16: 443–450.
81. Nana-Sinkam SP, Deog Lee J, Sotto-Santiago S, Stearman RS, Keith RL, Choudhury O, Cool C, Parr J, Moore MD, Bull TM, Voelkel NF, Geraci MW. Prostacyclin prevents pulmonary cell apoptosis induced by cigarette smoke. Am J Respir Crit Care Med. 2007; 175: 676–685.
82. Lanas A, Bajador E, Serrano P, Fuentes J, Carreno S, Guardia J, Sanz M, Montoro M, Sainz R. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med. 2000; 343: 834–839.
83. ADIS R&D profile. Nitronaproxen: AZD 3582, HCT 3012, Naproxen, Nitroxybutylester, NO-Naproxen. Drugs R D. 2006; 7: 262–266.[CrossRef][Medline] [Order article via Infotrieve]
84. Chegaev K, Lazzarato L, Tosco P, Cena C, Marini E, Rolando B, Carrupt P-A, Fruttero R, Gasco A. NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties. J Med Chem. 2007; 50: 1449–1457.[CrossRef][Medline] [Order article via Infotrieve]
85. Bolla M, Momi S, Gresele P, Del Soldato P. Nitric oxide-donating aspirin (NCX 4016): an overview of its pharmacological properties and clinical perspectives. Eur J Clin Pharmacol. 2006; 62: 145–154.[CrossRef]
This article has been cited by other articles:
 |
|
 |
|
  T. Matsumoto, N. Nakayama, K. Ishida, T. Kobayashi, and K. Kamata Eicosapentaenoic Acid Improves Imbalance between Vasodilator and Vasoconstrictor Actions of Endothelium-Derived Factors in Mesenteric Arteries from Rats at Chronic Stage of Type 2 Diabetes J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 324 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Barrios, C. Escobar, R. Echarri, and J. J. Jimenez-Nacher Antihypertensive drugs in daily clinical practice: are there differences between genders? Eur. Heart J., March 1, 2009; 30(5): 624 - 624. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hawfield and B. I. Freedman Pre-eclampsia: the pivotal role of the placenta in its pathophysiology and markers for early detection Therapeutic Advances in Cardiovascular Disease, February 1, 2009; 3(1): 65 - 73. [Abstract] [PDF]
|
|
|
|
 |
|
 S. H.H. Chan, K. L.H. Wu, A. Y.W. Chang, M.-H. Tai, and J. Y.H. Chan Oxidative Impairment of Mitochondrial Electron Transport Chain Complexes in Rostral Ventrolateral Medulla Contributes to Neurogenic Hypertension Hypertension, February 1, 2009; 53(2): 217 - 227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Lamon and D. P. Hajjar Inflammation at the Molecular Interface of Atherogenesis: An Anthropological Journey Am. J. Pathol., November 1, 2008; 173(5): 1253 - 1264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fava, M. Montagnana, P. Almgren, L. Rosberg, G. Lippi, B. Hedblad, G. Engstrom, G. Berglund, P. Minuz, and O. Melander The V433M Variant of the CYP4F2 Is Associated With Ischemic Stroke in Male Swedes Beyond Its Effect on Blood Pressure Hypertension, August 1, 2008; 52(2): 373 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Barrios, C. Escobar, R. Echarri, and A. Matali Gender and Blood Pressure Control Hypertension, June 1, 2008; 51(6): e48 - e48. [Full Text] [PDF]
|
|
|
|
|
|
J. Scobie, S. Keyhani, P. L. Hebert, and M. A. McLaughlin Response to Gender and Blood Pressure Control Hypertension, June 1, 2008; 51(6): e49 - e49. [Full Text] [PDF]
|
|
|
|
 |
|
 J. S Cnossen, K. C Vollebregt, N. d. Vrieze, G. t. Riet, B. W J Mol, A. Franx, K. S Khan, and J. A M v. d. Post Accuracy of mean arterial pressure and blood pressure measurements in predicting pre-eclampsia: systematic review and meta-analysis BMJ, May 17, 2008; 336(7653): 1117 - 1120. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||