This Article Abstract Full Text (PDF) All Versions of this Article: 45/2/163    most recent 01.HYP.0000153321.13792.b9v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Watanabe, T. Articles by Berk, B. C. Search for Related Content PubMed PubMed Citation Articles by Watanabe, T. Articles by Berk, B. C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Signal transduction Endothelium/vascular type/nitric oxide

(Hypertension. 2005;45:163.)
© 2005 American Heart Association, Inc.

Brief Review

Angiotensin II and the Endothelium

Diverse Signals and Effects

Tetsu Watanabe; Thomas A. Barker; Bradford C. Berk

From the Center for Cardiovascular Research, University of Rochester, New York.

Correspondence to Bradford C. Berk, MD, PhD, Center for Cardiovascular Research, University of Rochester, Box 679, 601 Elmwood Ave, Rochester, NY 14642. E-mail bradford_berk{at}urmc.rochester.edu

	Abstract

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
The initial view of the renin-angiotensin system focused on the role of angiotensin II as a hormone involved in blood pressure control, based on its role in renal salt and water regulation, as well as central nervous system (thirst) and vascular smooth muscle tone. Subsequent data showed a role for angiotensin II in long-term effects on cardiovascular structure, including cardiac hypertrophy and vascular remodeling. Importantly, recent human studies with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have demonstrated exciting clinical benefits including decreases in incidence of stroke, diabetes, and end-stage renal disease that suggest important new mechanisms of action. In this review, we focus on new roles for the renin-angiotensin system in the endothelium based on the concepts of diverse signals and effects mediated by multiple angiotensin I- and angiotensin II-derived peptides, multiple angiotensin metabolizing enzymes, multiple receptors, and vascular bed-specific intracellular signals.

Key Words: angiotensin II • endothelium • signal transduction

	Introduction

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
In this review, we discuss the evolving role of angiotensin II (Ang II) as a regulator of endothelial cell (EC) function. In particular, recent clinical trials of angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor blockers (ARBs) suggest that several of the beneficial effects of these drugs are mediated by inhibiting Ang II effects at the endothelium. Initially, Ang II was identified as a hormone that controlled blood pressure based on regulation of renal salt and water metabolism, central nervous system mechanisms (thirst and sympathetic outflow), and vascular smooth muscle cell (VSMC) tone.¹ Later, Ang II was found to exert long-term effects on tissue structure, including cardiac hypertrophy, vascular remodeling, and renal fibrosis. Importantly, recent human studies with ACE inhibitors and ARBs have yielded exciting clinical benefits such as decreased incidence of stroke, diabetes mellitus, and end-stage renal disease.^2,3 This article discusses the endothelium-specific effects of these drugs and Ang II, based on the concept of diverse signals and effects mediated by multiple angiotensin receptors (AT₁R, AT₂R, and AT₄R), multiple angiotensin I- and Ang II-derived peptides [Ang III, Ang IV, and Ang (1–7)], and vascular bed-specific events (Figure 1). The enzymes that control generation of these peptides, including ACE, ACE2, endopeptidases, and aminopeptidases, interact with each other. In addition, drugs such as ACE inhibitors and ARBs that inhibit formation of Ang II and binding to its receptor also modify the expression of receptors for Ang II and of other vasoactive hormones, including bradykinin and adrenomedullin. This complex interplay of pathways helps to explain the findings that Ang II can have both beneficial and detrimental effects on vascular function.

View larger version (20K): [in this window] [in a new window]   Figure 1. Metabolism of angiotensinogen to generate the peptide hormones of the renin-angiotensin system.

	Effects of Angiotensin Type-1 Receptor

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
The AT₁R has been shown to mediate most of the physiological actions of Ang II. However, as discussed, important regulatory roles for the AT₂R and AT₄R, have been defined, especially in EC. Recent data show several pathways by which the AT₁R and AT₂R modulate EC function.⁴

Apoptosis
Ang II has been shown both to increase and decrease EC apoptosis, suggesting that other factors influence the actions of Ang II (eg, presence of oxidized low-density lipoprotein [oxLDL]). In fact, both the AT₁R and the AT₂R have been suggested to mediate EC apoptosis.^5,6 As discussed further, we speculate that the relative AT₁R and AT₂R expression levels are important determinants of the effects of Ang II in EC (Figure 2). Ang II-mediated EC apoptosis is in part mediated by generation of reactive oxygen species (ROS), because antioxidants suppress EC apoptosis. Ang II increases NADPH oxidase activity in EC, enhancing superoxide production via AT₁R and AT₂R.⁵ Ang II and ROS also promote EC apoptosis by inhibiting the function of the anti-apoptotic protein Bcl-2.⁶ For example, ROS generated by Ang II cause transcriptional downregulation of Bcl-2 and upregulation of pro-apoptotic Bax. In addition, Ang II was shown to inactivate extracellular signal-regulated kinase (ERK) (ERK1/2) by upregulating mitogen-activated protein kinase (MAPK) phosphatase 3, thereby decreasing Bcl-2.⁷ Ang II may indirectly cause EC apoptosis via induction of Fas and LOX-1.⁶ Finally, the AT₁R directly alters endothelial nitric oxide synthase (eNOS) function by binding to membrane-localized eNOS. Marrero et al showed that eNOS was bound and its activity was inhibited by the bradykinin B₂ receptor (B₂R), the AT₁R and the endothelin-1 ET_B receptor.⁸ The interaction is controlled in part by phosphorylation of serines and tyrosines that interact with eNOS, although the physiological importance and kinases involved remain to be clarified. In summary, Ang II promotes apoptosis in EC via direct and indirect mechanisms.

View larger version (23K): [in this window] [in a new window]   Figure 2. Proposed mechanism by which the relative levels of AT1R and AT2R expression affect EC angiogenesis.

Recently, Ang II was shown to inhibit microvascular EC apoptosis via AT₁R by activating PI3-kinase and Akt, which stimulated expression of an anti-apoptotic protein named survivin.⁹ The findings that Ang II has both proapoptotic and antiapoptotic effects may be a consequence of the growth state of EC, vascular bed-specific phenotype, and the nature of their interaction with extracellular matrix. For example, the initial phase of Ang II-mediated angiogenesis may require microvascular EC growth and migration, whereas subsequent maturation and pruning of the neovasculature may require EC differentiation and apoptosis.

Lectin-Like OxLDL Receptor-1
There is increasing evidence that Ang II modulates the effects of oxLDL on EC function, thereby promoting atherosclerosis. Uptake of oxLDL by EC impairs nitric oxide (NO) production, induces expression of white blood cell adhesion molecules, and promotes EC apoptosis. Lectin-like oxLDL receptor-1 (LOX-1) is a novel endothelial receptor for oxLDL that has been shown to mediate oxLDL-induced responses and uptake of oxLDL in EC.⁶ Activation of this pathway stimulates ROS production, MAPKs, and NF-B.⁶ In EC, Ang II via the AT₁R upregulates LOX-1, stimulates oxLDL uptake, and enhances oxLDL-mediated EC ROS generation and apoptosis.⁶ As part of a positive feedback mechanism, oxLDL also upregulates AT₁R (but not AT₂R) expression. As expected, ARBs and ACE inhibitors decrease LOX-1 expression in aortas from hypercholesterolemic rabbits¹⁰ and arteries from patients with coronary artery disease.¹¹ These data suggest important roles for LOX-1 and oxLDL in the effects of Ang II on EC function, especially EC apoptosis.

Plasminogen Activator Inhibitor Type 1
Plasminogen activator inhibitor type 1 (PAI-1) is the major physiological inhibitor of tissue-type plasminogen activator and urokinase-type plasminogen activator, and plays a key role in the regulation of thrombosis. Elevated PAI-1 is associated with myocardial infarction and atherosclerosis. Several experimental and clinical studies have shown that Ang II is a potent regulator of PAI-1 expression.¹² Ang II has been reported to increase PAI-1 mRNA and protein expression in EC.¹³ Some studies have reported that Ang II–induced PAI-1 expression is mediated by AT₁R¹⁴ via a pathway involving Rho/Rho kinase, cAMP, and ROS.¹⁵ AT₁R blockade with ARBs decreases PAI-1 antigen and PAI-1 activity in patients with chronic hypertension and heart failure, suggesting a key role for the AT₁R.¹⁶ However, as noted, the AT₄R may also be an important mediator of PAI-1 expression.¹³ Taken together, the evidence suggests that Ang II inhibits the fibrinolytic system via AT₁R by inducing PAI-1 expression in EC.

Cyclooxygenase-2 and Vascular Endothelial Growth Factor
Cyclooxygenase-2 (COX-2) is induced by many stimuli, including Ang II, and catalyzes the formation of prostaglandins and thromboxane A2.¹⁷ COX-2 expression in EC appears to be important in both atherosclerosis¹⁸ and angiogenesis.¹⁹ Mukai et al reported that ACE inhibitors and ARBs ameliorated endothelial dysfunction associated with aging through the inhibition of COX-2–derived eicosanoids.²⁰ In mouse models, overexpression of renin or angiotensinogen, as well as treatment with Ang II, induced COX-2 through the AT₁R, which led to EC dysfunction.²¹ Thus, COX-2 is an important mediator of Ang II effects on EC.

Ang II increases vascular endothelial growth factor (VEGF) via the AT₁R in EC and induces angiogenesis through both a COX-2 mediated inflammatory process and VEGF-related pathways.²¹ In addition, recent reports suggest that Ang II-induced VEGF expression is mediated by hypoxia-inducible factor-1 and causes vascular remodeling.²² Ang II-mediated increases in VEGF may be detrimental by increasing vascular permeability and edema formation. In summary, Ang II has powerful inflammatory effects on EC mediated by COX-2 and VEGF. These effects may be pathogenic by promoting accumulation of inflammatory cells and edema.

	Angiotensin Type-2 Receptor

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
There is growing evidence that the AT₂R plays an important role in cardiovascular physiology. Whereas the AT₁R is widely distributed throughout the body, the AT₂R is highly expressed only in the fetus, including early EC.²³ AT₂R expression decreases soon after birth to low levels, so that the predominant EC Ang II receptor is the AT₁R. However, in adult humans, low levels of AT₂R expression occur in aorta and coronary arteries.²⁴ It has become clear that the AT₂R participates in both normal physiology and cardiovascular disease. For example, AT₂R knockout mice have an exaggerated vasopressor response to Ang II.²⁵ AT₂R upregulation occurs in pathologic conditions such as in failing cardiomyopathic hearts²⁶ or after myocardial infarction.²⁷ Substantial evidence with the AT₂R knockout mouse indicates that the AT₂R protects both heart and brain tissue from ischemia. Specifically, the size of cerebral and myocardial infarction is significantly greater in the AT₂R knockout mouse.²⁸ In addition, the beneficial effects of ARBs on cardioprotection are mediated in part by an AT₂R-dependent pathway.

The AT₂R-pathway appears to protect tissues from ischemia via an AT₂R-bradykinin-NO-cyclic guanosine monophosphate (cGMP) pathway as shown in Figure 3.²⁹ As diagrammed, Ang II binding to the AT₂R inhibits the Na–H exchanger and promotes intracellular acidification. This activates a kininogenase that increases production of bradykinin, which now binds to the B₂R on both VSMC and EC. In EC, the B₂R increases eNOS activity, and NO stimulates cGMP and VSMC relaxation, a mechanism for AT₂R-dependent vasorelaxation. Although this pathway was initially described in VSMC and cardiomyocytes, similar pathways may occur in EC. Of interest, ARBs increase AT₂R expression in EC, which may be an important mechanism by which these drugs produce their effects. As shown in Figure 3, the increase in BK generated by the AT₂R stimulates eNOS and also increases the expression of extracellular superoxide dismutase. Extracellular superoxide dismutase decreases superoxide formation and thereby increases bioavailable NO. Finally, we have proposed that Ang II regulates the expression of eNOS and NO production, whereas NO downregulates AT₁R.³⁰ NO also regulates Ang II receptors in vitro. Treatment of rat VSMC with NO donors inhibited Ang II binding to cells, without altering receptor affinity.³⁰ However, treatment of the cells with cGMP analogs had no significant effect on Ang II binding, suggesting that NO regulates Ang II receptors through a cGMP-independent mechanism.³⁰ In VSMC, inhibition of Ang II binding by NO is caused by decreased AT1R mRNA expression and occurs at the transcriptional level.³¹ In addition, downstream effectors of Ang II and NO signaling pathways also interact with each other. In particular, cyclic nucleotide phosphodiesterases play critical roles in controlling intracellular cGMP levels by converting cGMP to 5'-GMP. Ang II exhibits inhibitory effects on cGMP accumulation elicited by NO donor or atrial natriuretic peptide in VSMC³² and vessels,³³ which is likely to be mediated by activation of Ca²⁺/CaM-stimulated phosphodiesterases. To date, very little is known regarding the roles of phosphodiesterases isoforms in Ang II–mediated effects on EC function.

View larger version (15K): [in this window] [in a new window]   Figure 3. Proposed mechanism by which the AT1R and AT2R interact with the kinin system in the vessel wall to control vascular tone.

The mechanisms for AT₂R signaling remain poorly described, especially in EC. A recent study by Gendron et al³⁴ in the neuronal cell line NG108 showed that Ang II–AT₂R-mediated neurite outgrowth involved activation of Rap1 and B-Raf, with stimulation of MAPK kinase-1 (MEK1) and ERK1/2. Exciting new data from Feng et al³⁵ showed that the AT₂R coupled to the G protein _s (G_s) independent of Gß and G. The authors found that SH2 domain-containing phosphatase 1 (SHP-1) constitutively associated with the AT₂R, and SHP-1 was activated on AT₂R stimulation by Ang II. These recent publications regarding the AT₂R demonstrate tissue specific pathways and involve protein tyrosine phosphatases, MAPK and G_s.

A simple generalization is that AT₁R and AT₂R signaling produce effects that are antagonistic. One mechanism that partially accounts for this is that the 2 receptors heterodimerize inhibiting AT₁R signaling.³⁶ This may have significance in Ang II effects on angiogenesis. AT₂R knockout mice exhibit impaired angiogenic potential,³⁷ but other studies have shown that AT₂R inhibits EC migration and is anti-angiogenic.³⁸ We propose an explanation for these contradictory results based on the relative levels of AT₁R and AT₂R expression (Figure 2). Normally, AT₁R expression is significantly greater than AT₂R expression and Ang II mediates angiogenesis. However, in response to tissue injury or drug treatment with ARBs, AT₂R expression increases and now heterodimerizes with AT₁R. Because this heterodimerization inhibits AT₁R signaling, AT₂R expression now is anti-angiogenic (Figure 2).

Similarly, we propose that the relative expression of these receptors may determine the effect of Ang II on EC apoptosis. The AT₂R has the ability to promote apoptosis independent of ligand binding in fibroblasts,³⁹ supporting the concept that receptor expression is important for its physiological outcome. The effects of this receptor on apoptosis are cell type-specific in that it has been shown to be anti-apoptotic in cardiomyocytes⁴⁰ but pro-apoptotic in VSMC.³⁹ There is less evidence for its role in EC, with the limited available data suggesting AT₂R signaling also promotes apoptosis.⁵ As the evidence grows, it may become apparent that heterodimerization plays an important role in this process (Figure 2).

	Effects of AT4R

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
Ang IV [Ang (3–8)] is an important angiotensin degradation peptide (Figure 1) that binds to the AT₄R, which is expressed primarily in EC. Upregulation of AT₄R was detected in the re-endothelialized cell layer after balloon injury.⁴¹ Ang IV has been shown to increase PAI-1 expression via the AT₄R.^13,15 An AT₄R blocker, but not AT₁R or AT₂R blockers, inhibited Ang IV–induced PAI-1 expression.^13,15 In addition, an aminopeptidase inhibitor suppressed Ang II-induced PAI-1 expression, suggesting a key role for metabolism of Ang II to generate Ang IV.¹³ Ang IV has been reported to mediate cerebral and pulmonary artery vasorelaxation via NO release⁴² and pulmonary microvascular EC proliferation.⁴³ Ruiz-Ortega et al suggested that Ang IV is proinflammatory because Ang IV activates NF-B.⁴⁴ To define the role of Ang IV in vascular disease, identification of the AT₄R will be necessary.

	ACE and Bradykinin in the Endothelium

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
Studies using transgenic mice have defined the role of ACE in cardiovascular physiology. ACE knockout mice are hypotensive, and arterial blood pressure closely follows ACE expression in partial knockouts.⁴⁵ Recently, endothelial ACE was specifically knocked-out in the ACE 1/3 mice.⁴⁶ Although these mice are normotensive under basal conditions, when the mice were stressed by a low-salt diet they became hypotensive compared with wild-type controls. These studies show that endothelial ACE is important, but not essential, for normal blood pressure regulation.

ACE is a major link between the renin-angiotensin system and the kinin systems, because it not only converts Ang I to Ang II but also degrades kinins (Figure 1). ECs are an important site for the effects of BK and have been shown to express both B₁R and B₂R. ACE inhibitors potentiate the actions of BK by reducing its degradation, which causes an increase in BK binding to EC receptors.⁴⁷ In addition, ACE inhibitors alter B₂R binding site affinities and targeting to caveolin-rich areas of the membrane, illustrating another regulatory link between the renin-angiotensin system and the kinin system.⁴⁸

	ACE-Related Carboxypeptidase

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
Recently, a homologue of ACE, termed ACE-related carboxypeptidase (ACE2) has been identified.⁴⁹ ACE2 is a membrane-associated, zinc metalloprotease expressed predominantly on endothelium in heart, kidney, and testis.⁴⁹ ACE2 has been shown to convert Ang I and Ang II into Ang (1–9) and Ang (1–7), respectively (Figure 1).⁵⁰ Ang (1–7) is an active peptide that has been shown to be a potent vasodilator. Ang (1–7) potentiates BK actions through the release of prostaglandins, NO, or endothelium-derived hyperpolarizing factor.⁵¹ Ang (1–7) also possesses antitrophic and anti-inflammatory effects. Although Ang II is a potent stimulus for PAI-1, Ang (1–7) decreases PAI-1 expression in EC.⁵² Deletion of ACE2 results in a severe cardiac contractility defect that may be associated with changes in the cardiac renin-angiotensin system.⁵³ In addition, ACE2 hydrolyzes apelin 13 and dynorphin A with comparable catalytic efficiency to the conversion of Ang II to Ang (1–7). Apelin has been identified as an endogenous ligand for APJ (a putative receptor protein related to the AT₁R) that is a G protein-coupled receptor.⁵⁴ Although APJ has 31% amino acid sequence homology with the AT₁R, it does not exhibit specific binding of Ang II. Recently, it was shown that binding of apelin to APJ has vasodilative effects in vivo and may play a counter-regulatory role to Ang II.⁵⁵ These results suggest that ACE2 interacts with Ang II and bradykinin pathways and may modulate the renin-angiotensin system by multiple mechanisms.

	ACE Inhibitors

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
There is strong evidence that inhibiting ACE activity has clinical benefits to limit cardiovascular events including myocardial infarction, congestive heart failure, and stroke.^2,56,57 ACE inhibitors work in part by improving endothelial dysfunction.⁵⁸ ACE inhibitors have been shown to increase arterial dilation via B₂R-NO-pathways.⁵⁹ ACE inhibitors also improve EC survival after hypoxic injury via B₂R-NO–dependent pathways.⁶⁰ In addition, these drugs induce B₁R in the renal vasculature and increase NO production from EC expressing these receptors.⁶¹ Recently, a novel mechanism for ACE inhibitors has been discovered that involves signal transduction by ACE itself (Figure 4). Specifically, the protein kinase, CK2, was found to phosphorylate the cytoplasmic tail of ACE, thereby activating intracellular signaling via JNK. ACE inhibitors potentiate this signaling, which may be another mechanism by which these drugs produce their beneficial effects.⁶²

View larger version (12K): [in this window] [in a new window]   Figure 4. Multiple effect of ACE inhibitors and ARBs on ECs. Note that ARB refers to metabolites of ARBs (eg, EXP3174 and EXP3179 derived from losartan) that may have AT1R-independent effects on EC function.

	ARB Effects

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
Recently, 3 randomized studies compared the clinical benefits of ARBs in patients with hypertension to other types of antihypertensive therapy: the Losartan Intervention For Endpoint reduction in hypertension (LIFE),³ Study on COgnition and Prognosis in the Elderly (SCOPE),⁶³ and Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trials.⁶⁴ In the LIFE trial, 9193 hypertensive patients with left ventricular hypertrophy were randomized to the ARB losartan or the ß-blocker atenolol plus conventional therapy.³ The results showed a significant beneficial effect of losartan on total mortality as well as stroke, despite similar reductions of blood pressure in the 2 groups. Similarly, there was a significant 28% reduction of nonfatal stroke in the SCOPE trial, which compared candesartan to placebo in 4964 elderly patients with hypertension.⁶³ In VALUE, 15 245 hypertensive patients were randomized to the ARB valsartan or the calcium antagonist amlodipine. The results of the VALUE trial showed that valsartan was associated with a slightly higher incidence of stroke and myocardial infarction, particularly during the first 6 months of the study, which was apparently associated with a slower reduction in blood pressure.⁶⁴ However, at study end (mean, 4.2 years), there was no difference in the primary composite end point of cardiac morbidity and mortality.

Likely explanations for blood pressure-independent effects of ARBs in LIFE trial are improved endothelial function caused by decreased coagulation and inflammation and altered vessel structure. For example, Schiffrin et al demonstrated that endothelium-dependent relaxation and the media/lumen ratio of resistance arteries from hypertensive patients were normalized after 1 year by losartan but not by atenolol.⁶⁵ Recently, several articles have shown that some ARBs have AT₁R-independent anticoagulant and anti-inflammatory effects.^17,66 Krämer et al¹⁷ demonstrated that the losartan metabolite EXP3179, which has no AT₁R-blocking properties, inhibited expression of COX-2 and suppressed thromboxane A2-induced platelet aggregation. We found that losartan and EXP3179 activated Akt, increased eNOS phosphorylation, and prevented EC apoptosis.⁶⁷ These AT₁R-independent actions may be related to the individual chemical characteristics of losartan and irbesartan rather than to an ARB class effect.^17,66 AT₁R-independent effects of other ARBs remain to be investigated.

Recently, 2 groups suggested that PPAR activation represents a novel mechanism for the beneficial effects of ARBs.^68,69 Irbesartan and telmisartan potently enhanced PPAR-dependent adipocyte differentiation associated with increases in mRNA expression of PPAR-responsive genes. The PPAR-activating properties differed, with EC₅₀ values ranging from low (telmisartan), to medium (irbesartan), to very high (losartan). These differences among ARBs are likely caused by their physicochemical properties, because high lipophilicity (telmisartan is highest) is required to obtain sufficiently high penetration rates to bind to intracellular PPAR. When PPAR-activating ARBs were compared with the PPAR ligand pioglitazone, the ARBs behaved like partial PPAR agonists, suggesting tissue and concentration-specific effects.⁶⁹ To date, little is known regarding the effects of ARBs on PPAR function in EC.

	Summary and Conclusions

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 
Exciting new findings suggest novel roles for angiotensin peptides and the angiotensin receptors (AT₁R, AT₂R, and AT₄R) present on EC. An important concept highlighted in this review is the extensive cross-talk between bradykinin (generated in increased levels in the presence of ACE inhibition) and the AT₂R (Figure 4). It appears well-established that many beneficial effects of ACE inhibition require AT₂R-dependent increases in NO. In addition, we discussed several novel mechanisms by which the AT₂R may directly regulate the AT₁R, including signal transduction by phosphatases and heterodimerization. Equally exciting are recent discoveries for ACE inhibitors and ARBs that suggest actions independent of their primary mechanism of action: ACE signaling to JNK and activation of multiple AT₁R-independent pathways for ARBs (Figure 4). The novel ARB pathways include binding of metabolites to the thromboxane A2 receptor, activation of eNOS by stimulation of a PI3-kinase/Akt pathway, and activation of PPAR. These new mechanisms may account for some of the unique clinical benefits of ARBs to decrease stroke, diabetes, and end-stage renal disease. It is now clear that the endothelium is an important target for the renin-angiotensin system and for the action of ACE inhibitors and ARBs.

Received October 4, 2004; first decision October 15, 2004; accepted December 2, 2004.

	References

Top Abstract Introduction Effects of Angiotensin Type-1... Angiotensin Type-2 Receptor Effects of AT4R ACE and Bradykinin in... ACE-Related Carboxypeptidase ACE Inhibitors ARB Effects Summary and Conclusions References

 

1. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000; 52: 11–34.[Abstract/Free Full Text]
2. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators [comment]. [erratum appears in 2000 May 4;342(18):1376]. N Engl J Med. 2000; 342: 145–153.[Abstract/Free Full Text]
3. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 995–1003.[CrossRef][Medline] [Order article via Infotrieve]
4. Berk BC. Angiotensin type 2 receptor (AT2R): a challenging twin. Science STKE. 2003; 2003: PE16.
5. Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM. Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res. 1997; 81: 970–976.[Abstract/Free Full Text]
6. Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL. Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res. 1999; 84: 1043–1049.[Abstract/Free Full Text]
7. Dimmeler S, Zeiher AM. Reactive oxygen species and vascular cell apoptosis in response to angiotensin II and pro-atherosclerotic factors. Regul Pept. 2000; 90: 19–25.[CrossRef][Medline] [Order article via Infotrieve]
8. Marrero MB, Venema VJ, Ju H, He H, Liang H, Caldwell RB, Venema RC. Endothelial nitric oxide synthase interactions with G-protein-coupled receptors. Biochem J. 1999; 343 (Pt 2): 335–340.[CrossRef][Medline] [Order article via Infotrieve]
9. Ohashi H, Takagi H, Oh H, Suzuma K, Suzuma I, Miyamoto N, Uemura A, Watanabe D, Murakami T, Sugaya T, Fukamizu A, Honda Y. Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothelial cells by governing survivin expression and suppression of caspase-3 activity. Circ Res. 2004; 94: 785–793.[Abstract/Free Full Text]
10. Chen H, Li D, Sawamura T, Inoue K, Mehta JL. Upregulation of LOX-1 expression in aorta of hypercholesterolemic rabbits: modulation by losartan. Biochem Biophys Res Commun. 2000; 276: 1100–1104.[CrossRef][Medline] [Order article via Infotrieve]
11. Morawietz H, Rueckschloss U, Niemann B, Duerrschmidt N, Galle J, Hakim K, Zerkowski HR, Sawamura T, Holtz J. Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein. Circulation. 1999; 100: 899–902.[Abstract/Free Full Text]
12. Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation. 1993; 87: 1969–1973.[Abstract/Free Full Text]
13. Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest. 1995; 96: 2515–2520.[Medline] [Order article via Infotrieve]
14. Nishimura H, Tsuji H, Masuda H, Nakagawa K, Nakahara Y, Kitamura H, Kasahara T, Sugano T, Yoshizumi M, Sawada S, Nakagawa M. Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. Thromb Haemost. 1997; 77: 1189–1195.[Medline] [Order article via Infotrieve]
15. Mehta JL, Li DY, Yang H, Raizada MK. Angiotensin II and IV stimulate expression and release of plasminogen activator inhibitor-1 in cultured human coronary artery endothelial cells. J Cardiovasc Pharmacol. 2002; 39: 789–794.[CrossRef][Medline] [Order article via Infotrieve]
16. Brown NJ, Kumar S, Painter CA, Vaughan DE. ACE Inhibition Versus Angiotensin Type 1 Receptor Antagonism: Differential Effects on PAI-1 Over Time. Hypertension. 2002; 40: 859–865.[Abstract/Free Full Text]
17. Kramer C, Sunkomat J, Witte J, Luchtefeld M, Walden M, Schmidt B, Boger RH, Forssmann WG, Drexler H, Schieffer B. Angiotensin II receptor-independent antiinflammatory and antiaggregatory properties of losartan: role of the active metabolite EXP3179. Circ Res. 2002; 90: 770–776.[Abstract/Free Full Text]
18. 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.[Abstract/Free Full Text]
19. Dormond O, Ruegg C. Regulation of endothelial cell integrin function and angiogenesis by COX-2, cAMP and Protein Kinase A. Thromb Haemost. 2003; 90: 577–585.[Medline] [Order article via Infotrieve]
20. Mukai Y, Shimokawa H, Higashi M, Morikawa K, Matoba T, Hiroki J, Kunihiro I, Talukder HM, Takeshita A. Inhibition of renin-angiotensin system ameliorates endothelial dysfunction associated with aging in rats. Arterioscler Thromb Vasc Biol. 2002; 22: 1445–1450.[Abstract/Free Full Text]
21. Tamarat R, Silvestre JS, Durie M, Levy BI. Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest. 2002; 82: 747–756.[Medline] [Order article via Infotrieve]
22. Page EL, Robitaille GA, Pouyssegur J, Richard DE. Induction of Hypoxia-inducible Factor-1alpha by Transcriptional and Translational Mechanisms. J Biol Chem. 2002; 277: 48403–48409.[Abstract/Free Full Text]
23. Aguilera G, Kapur S, Feuillan P, Sunar-Akbasak B, Bathia AJ. Developmental changes in angiotensin II receptor subtypes and AT1 receptor mRNA in rat kidney. Kidney Int. 1994; 46: 973–979.[Medline] [Order article via Infotrieve]
24. Batenburg WW, Garrelds IM, Bernasconi CC, Juillerat-Jeanneret L, Van Kats JP, Saxena PR, Danser AH. Angiotensin II Type 2 Receptor-Mediated Vasodilation in Human Coronary Microarteries. Circulation. 2004.
25. Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BL, Inagami T. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature. 1995; 377: 748–750.[CrossRef][Medline] [Order article via Infotrieve]
26. Ohkubo N, Matsubara H, Nozawa Y, Mori Y, Murasawa S, Kijima K, Maruyama K, Masaki H, Tsutumi Y, Shibazaki Y, Iwasaka T, Inada M. Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation. 1997; 96: 3954–3962.[Abstract/Free Full Text]
27. Wharton J, Morgan K, Rutherford RA, Catravas JD, Chester A, Whitehead BF, De Leval MR, Yacoub MH, Polak JM. Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. J Pharmacol Exp Ther. 1998; 284: 323–336.[Abstract/Free Full Text]
28. Iwai M, Liu HW, Chen R, Ide A, Okamoto S, Hata R, Sakanaka M, Shiuchi T, Horiuchi M. Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation. Circulation. 2004; 110: 843–848.[Abstract/Free Full Text]
29. Tsutsumi Y, Matsubara H, Masaki H, Kurihara H, Murasawa S, Takai S, Miyazaki M, Nozawa Y, Ozono R, Nakagawa K, Miwa T, Kawada N, Mori Y, Shibasaki Y, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Takahashi H, Iwasaka T. Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest. 1999; 104: 925–935.[Medline] [Order article via Infotrieve]
30. Yan C, Kim D, Aizawa T, Berk BC. Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator. Arterioscler Thromb Vasc Biol. 2003; 23: 26–36.[Abstract/Free Full Text]
31. Ichiki T, Usui M, Kato M, Funakoshi Y, Ito K, Egashira K, Takeshita A. Downregulation of angiotensin II type 1 receptor gene transcription by nitric oxide. Hypertension. 1998; 31: 342–348.[Abstract/Free Full Text]
32. Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, Beavo JA, Berk BC, Yan C. Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Circulation. 2001; 104: 2338–2343.[Abstract/Free Full Text]
33. Molina CR, Andresen JW, Rapoport RM, Waldman S, Murad F. Effect of in vivo nitroglycerin therapy on endothelium-dependent and independent vascular relaxation and cyclic GMP accumulation in rat aorta. J Cardiovasc Pharmacol. 1987; 10: 371–378.[Medline] [Order article via Infotrieve]
34. Gendron L, Oligny JF, Payet MD, Gallo-Payet N. Cyclic AMP-independent involvement of Rap1/B-Raf in the angiotensin II AT2 receptor signaling pathway in NG108–15 cells. J Biol Chem. 2002; 2: 2.
35. Feng YH, Sun Y, Douglas JG. Gbeta gamma-independent constitutive association of Galpha s with SHP- 1 and angiotensin II receptor AT2 is essential in AT2-mediated ITIM- independent activation of SHP-1. Proc Natl Acad Sci S A. 2002; 99: 12049–12054.
36. AbdAlla S, Lother H, Abd El Tawaab A, Quitterer U. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem. 2001; 15: 15.
37. Walther T, Menrad A, Orzechowski HD, Siemeister G, Paul M, Schirner M. Differential regulation of in vivo angiogenesis by angiotensin II receptors. FASEB J. 2003; 17: 2061–2067.[Abstract/Free Full Text]
38. Silvestre JS, Tamarat R, Senbonmatsu T, Icchiki T, Ebrahimian T, Iglarz M, Besnard S, Duriez M, Inagami T, Levy BI. Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. Circ Res. 2002; 90: 1072–1079.[Abstract/Free Full Text]
39. Miura S, Karnik SS. Ligand-independent signals from angiotensin II type 2 receptor induce apoptosis. EMBO J. 2000; 19: 4026–4035.[CrossRef][Medline] [Order article via Infotrieve]
40. Sugino H, Ozono R, Kurisu S, Matsuura H, Ishida M, Oshima T, Kambe M, Teranishi Y, Masaki H, Matsubara H. Apoptosis is not increased in myocardium overexpressing type 2 angiotensin II receptor in transgenic mice. Hypertension. 2001; 37: 1394–1398.[Abstract/Free Full Text]
41. Moeller I, Clune EF, Fennessy PA, Bingley JA, Albiston AL, Mendelsohn FA, Chai SY. Up regulation of AT4 receptor levels in carotid arteries following balloon injury. Regul Pept. 1999; 83: 25–30.[CrossRef][Medline] [Order article via Infotrieve]
42. Patel JM, Martens JR, Li YD, Gelband CH, Raizada MK, Block ER. Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation. Am J Physiol. 1998; 275: L1061–L1068.[Medline] [Order article via Infotrieve]
43. Li YD, Block ER, Patel JM. Activation of multiple signaling modules is critical in angiotensin IV-induced lung endothelial cell proliferation. Am J Physiol Lung Cell Mol Physiol. 2002; 283: L707–L716.[Abstract/Free Full Text]
44. Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Suzuki Y, Mezzano S, Plaza JJ, Egido J. Role of the renin-angiotensin system in vascular diseases: expanding the field. Hypertension. 2001; 38: 1382–1387.[Abstract/Free Full Text]
45. Carlson SH, Oparil S, Chen YF, Wyss JM. Blood pressure and NaCl-sensitive hypertension are influenced by angiotensin-converting enzyme gene expression in transgenic mice. Hypertension. 2002; 39: 214–218.[Abstract/Free Full Text]
46. Cole JM, Khokhlova N, Sutliff RL, Adams JW, Disher KM, Zhao H, Capecchi MR, Corvol P, Bernstein KE. Mice lacking endothelial ACE: normal blood pressure with elevated angiotensin II. Hypertension. 2003; 41: 313–321.[Abstract/Free Full Text]
47. Linz W, Wiemer G, Scholkens BA. ACE-inhibition induces NO-formation in cultured bovine endothelial cells and protects isolated ischemic rat hearts. J Mol Cell Cardiol. 1992; 24: 909–919.[CrossRef][Medline] [Order article via Infotrieve]
48. Benzing T, Fleming I, Blaukat A, Muller-Esterl W, Busse R. Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells. Circulation. 1999; 99: 2034–2040.[Abstract/Free Full Text]
49. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res. 2000; 87: E1–E9.[Medline] [Order article via Infotrieve]
50. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000; 275: 33238–33243.[Abstract/Free Full Text]
51. Ferrario CM. Contribution of angiotensin-(1–7) to cardiovascular physiology and pathology. Curr Hypertens Rep. 2003; 5: 129–134.[Medline] [Order article via Infotrieve]
52. Yoshida M, Naito Y, Urano T, Takada A, Takada Y. L-158,809 and (D-Ala(7))-angiotensin I/II (1–7) decrease PAI-1 release from human umbilical vein endothelial cells. Thromb Res. 2002; 105: 531–536.[CrossRef][Medline] [Order article via Infotrieve]
53. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, da Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Backx PH, Yagil Y, Penninger JM. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002; 417: 822–828.[CrossRef][Medline] [Order article via Infotrieve]
54. Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun. 1998; 251: 471–476.[CrossRef][Medline] [Order article via Infotrieve]
55. Ishida J, Hashimoto T, Hashimoto Y, Nishiwaki S, Iguchi T, Harada S, Sugaya T, Matsuzaki H, Yamamoto R, Shiota N, Okunishi H, Kihara M, Umemura S, Sugiyama F, Yagami K, Kasuya Y, Mochizuki N, Fukamizu A. Regulatory Roles for APJ, a Seven-transmembrane Receptor Related to Angiotensin-type 1 Receptor in Blood Pressure in Vivo. J Biol Chem. 2004; 279: 26274–26279.[Abstract/Free Full Text]
56. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987; 316: 1429–1435.[Abstract]
57. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991; 325: 293–302.[Abstract]
58. Schlaifer JD, Wargovich TJ, O’Neill B, Mancini GB, Haber HE, Pitt B, Pepine CJ. Effects of quinapril on coronary blood flow in coronary artery disease patients with endothelial dysfunction. TREND Investigators. Trial on Reversing Endothelial Dysfunction. Am J Cardiol. 1997; 80: 1594–1597.[CrossRef][Medline] [Order article via Infotrieve]
59. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin- converting enzyme inhibitors in humans. Circulation. 1997; 95: 1115–1118.[Abstract/Free Full Text]
60. Fujita N, Manabe H, Yoshida N, Matsumoto N, Ochiai J, Masui Y, Uemura M, Naito Y, Yoshikawa T. Inhibition of angiotensin-converting enzyme protects endothelial cell against hypoxia/reoxygenation injury. Biofactors. 2000; 11: 257–266.[Medline] [Order article via Infotrieve]
61. Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, Erdos EG. Novel Mode of Action of Angiotensin I Converting Enzyme Inhibitors. Direct activation of bradykinin B1 receptor. J Biol Chem. 2002; 277: 16847–16852.[Abstract/Free Full Text]
62. Kohlstedt K, Brandes RP, Muller-Esterl W, Busse R, Fleming I. Angiotensin-converting enzyme is involved in outside-in signaling in endothelial cells. Circ Res. 2004; 94: 60–67.[Abstract/Free Full Text]
63. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003; 21: 875–886.[CrossRef][Medline] [Order article via Infotrieve]
64. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004; 363: 2022–2031.[CrossRef][Medline] [Order article via Infotrieve]
65. Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation. 2000; 101: 1653–1659.[Abstract/Free Full Text]
66. Li P, Fukuhara M, Diz DI, Ferrario CM, Brosnihan KB. Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation. J Pharmacol Exp Ther. 2000; 292: 238–246.[Abstract/Free Full Text]
67. Watanabe T, Berk B. Losartan stimulates phosphorylation of Akt and endothelial nitric oxide synthase in endothelial cells independently of angiotensin type 1 receptor blockade. Circulation. 2004; 110: 1124(Abstract).
68. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation. 2004; 109: 2054–2057.[Abstract/Free Full Text]
69. Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA, Kurtz TW. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension. 2004; 43: 993–1002.[Abstract/Free Full Text]

This article has been cited by other articles:

				J. Pang, C. Yan, K. Natarajan, M. E. Cavet, M. P. Massett, G. Yin, and B. C. Berk GIT1 Mediates HDAC5 Activation by Angiotensin II in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2008; 28(5): 892 - 898. [Abstract] [Full Text] [PDF]

				N. Y. Tan, V. C. Midgley, M. M. Kavurma, F. S. Santiago, X. Luo, R. Peden, R. G. Fahmy, M. C. Berndt, M. P. Molloy, and L. M. Khachigian Angiotensin II-Inducible Platelet-Derived Growth Factor-D Transcription Requires Specific Ser/Thr Residues in the Second Zinc Finger Region of Sp1 Circ. Res., February 29, 2008; 102(4): e38 - e51. [Abstract] [Full Text] [PDF]

				S. Brili, D. Tousoulis, C. Antoniades, C. Vasiliadou, M. Karali, N. Papageorgiou, N. Ioakeimidis, K. Marinou, E. Stefanadi, and C. Stefanadis Effects of Ramipril on Endothelial Function and the Expression of Proinflammatory Cytokines and Adhesion Molecules in Young Normotensive Subjects With Successfully Repaired Coarctation of Aorta A Randomized Cross-Over Study. J. Am. Coll. Cardiol., February 19, 2008; 51(7): 742 - 749. [Abstract] [Full Text] [PDF]