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(Hypertension. 1995;25:155-161.)
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Articles

Hypertension and the Pathogenesis of Atherosclerosis

Oxidative Stress and the Mediation of Arterial Inflammatory Response: A New Perspective

R. Wayne Alexander

From the Division of Cardiology, Emory University School of Medicine, Atlanta, Ga.

Correspondence to R. Wayne Alexander, Division of Cardiology, Emory University School of Medicine, PO Drawer LL, Atlanta, GA 30322.

	Abstract

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Abstract Hypertension is a risk factor for the development of atherosclerosis, although the mechanisms have not been well elucidated. As the cellular and molecular mechanisms of the pathogenesis of atherosclerosis and the effects of hypertension are being more clearly defined, it becomes apparent that the two processes have certain common mechanisms. The endothelium is a likely central focus for the effect of both diseases. There is increasing evidence that atherosclerosis should be viewed fundamentally as an inflammatory disease. Atherogenic stimuli such as hyperlipidemia appear to activate the inflammatory response by causing expression of mononuclear leukocyte recruiting mechanisms. The gene for one of these, the vascular cell adhesion molecule-1, is controlled at least in part by transcriptional factors regulated by oxidative stress, which modifies the redox state of the endothelial cell. Alterations in the redox state of the arterial wall also may contribute to vascular smooth muscle cell growth. In a somewhat parallel fashion, there is evidence that hypertension may also exert oxidative stress on the arterial wall. This article reviews evidence that leads to the postulate that hypertension predisposes to and accelerates atherosclerosis at least in part because of synergy between elevated blood pressure and other atherogenic stimuli to induce oxidative stress on the arterial wall.

Key Words: atherosclerosis • hypertension, essential • endothelium • muscle, smooth, vascular • stress

	Introduction

Top Abstract Introduction The Importance of the... Hyperlipidemia and... Atherosclerosis as an... The Effects of Hypertension... Hypertension and Atherosclerosis... Summary and Conclusions References

 
Hypertension is not only a well-established cardiovascular risk factor but also increases the risk of atherosclerosis. Clinical trials have shown that, in the highest quintile of diastolic pressure, even with the added risks of high cholesterol and smoking, hypertension still contributes significantly to risk for atherosclerosis.^{1 2} In laboratory studies in which hypertension was induced in the Watanabe heritable hyperlipidemic rabbit, Chobanian and his group³ showed a synergistic effect that caused an intensification of atherosclerosis. In the total surface area of involvement of the abdominal aorta of these endogenously hypercholesterolemic animals, a dramatic enhancement of lesion formation accompanied the induced hypertension. The low-density lipoprotein (LDL) receptor in this rabbit strain has the same type of molecular defect as is found in familial hypercholesterolemia. Thus, both clinical and experimental data show that high (elevated) blood pressure enhances the development of atherosclerosis. In fact, atherosclerosis tends to occur only in those parts of the vascular system subjected to high pressure.

However, the mechanisms of this enhanced or synergistic effect are not yet well defined. We still do not understand the fundamental nature of atherosclerosis itself, although great progress has been made, especially recently, in understanding and developing some unifying hypotheses about the pathogenesis of the disease. This conceptual process, in turn, has made it easier to begin to develop mechanistic insights into the role of hypertension in exacerbating the atherosclerotic process.

Atherosclerosis and hypertension are distinct disease entities; everyone who has hypertension does not manifest extensive atherosclerosis, nor is atherosclerosis always or even usually accompanied by hypertension. The cardinal pathological features of atherosclerotic lesion development are (1) the presence of monocytes/macrophages and T cells, (2) their localization in large conduit or elastic arteries in areas of low shear stress, (3) proliferation and migration to the intima of medial smooth muscle cells, (4) the deposition of increased amounts of connective tissue, and (5) neovascularization.⁴ Hypertensive arteries are thickened, and there may be increased smooth muscle cell mass and/or cell number and increased deposition of connective tissue.⁵ In considering the interactions of the two diseases, it will probably be most useful to consider mechanisms or consequences that are common to both. The purpose of this review is to relate recently developed concepts of the pathogenesis of atherosclerosis to shared mechanisms in hypertension, with a focus on the molecular mechanism by which hypertension might facilitate the development or progression of atherosclerosis. The subject has been reviewed extensively in broader contexts.^{5 6 7 8}

	The Importance of the Endothelium

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The logical initial focus in considering shared pathophysiological mechanisms is the endothelium, which has been intensely studied for the last 15 to 20 years. Abnormalities of the endothelium underlie a number of human diseases and appear to be central to the pathogenesis of atherosclerosis. Changes in endothelial function and morphology are also cardinal features of hypertension.⁹ New knowledge about common features of the endothelium in atherosclerosis and hypertension may contribute to understanding the effect of elevated blood pressure in the development of atherosclerosis.

The importance of the endothelium in the development of atherosclerosis was first appreciated when it was observed that its removal facilitated atherosclerotic lesion development in hypercholesterolemic animal models.¹⁰ These observations led to the "response to injury" hypothesis of atherosclerosis,¹⁰ in which it was assumed that endothelial desquamation preceded lesion development. It was shown subsequently, however, that the endothelium overlying lesions is intact but morphologically altered (except over very advanced, active lesions¹¹ ). These findings led to the concept of "dysfunction" of the endothelium.¹² The underlying assumption was that critical, initially unknown functions of the normal endothelium that protect against atherosclerotic lesion development go awry in the endothelial cells in lesion-prone areas.

The first direct evidence for endothelial dysfunction in human atherosclerosis actually came from clinical investigations into the disordered control of vasomotor tone in coronary artery disease.¹³ The hypothesis tested was that, whatever the nature of the putative endothelial dysfunction associated with the development of atherosclerosis, the abnormalities would be general and would extend to encompass the endothelium-dependent control of vasomotor tone. The phenomenon of endothelium-dependent vasodilation had been discovered earlier.¹⁴ The endothelium was shown to release a vasodilating humoral agent in response to various stimuli, including acetylcholine and blood flow. This agent was called endothelium-derived relaxing factor and subsequently was shown to be nitric oxide.^{15 16} Nitric oxide diffuses to the underlying vascular smooth muscle and causes relaxation by stimulating guanylate cyclase to increase cyclic GMP.¹⁷ In the cardiac catheterization laboratory, narrowed segments of coronary arteries in patients with angiographic evidence of atherosclerosis constricted in response to the endothelium-dependent vasodilator acetylcholine, whereas normal smooth segments dilated.¹³ Thus, the relation between atherosclerosis and dysfunctional endothelium was established. As will be discussed subsequently, the molecular mechanisms underlying the vasomotor dysfunction may also contribute to the pathogenesis of atherosclerosis. Certain of these molecular and metabolic abnormalities may also be characteristic of the hypertensive arterial wall.

	Hyperlipidemia and Atherosclerosis

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The intimate relation between hyperlipidemia and abnormal lipoprotein metabolism and atherosclerosis has been appreciated for many years.¹⁸ Indeed, the lipid-laden macrophage or foam cell is recognized as a hallmark of the disease. Despite the recognition of the association between hyperlipidemia and atherosclerosis, the precise molecular link has only recently begun to be elucidated. One of the seminal observations was that whereas native LDL was not taken up readily by macrophages, LDL that had been modified by exposure to endothelial cells was readily taken up and led to the formation of foam cells in vitro.¹⁹ It was subsequently established that one of the important modifications of LDL that permitted its recognition by the scavenger LDL receptor on macrophages was oxidative modification of the lipoprotein.²⁰ Oxidized LDL was found to have protean biological effects on the vessel wall, including stimulation of cytokine production,^{21 22} inhibition of endothelial cell vasodilator function,²³ and stimulation of growth factor production.²⁴ In addition to the importance of these observations in providing mechanistic links between lipoproteins and the cell biology of atherosclerosis, they raised the more general possibility that abnormalities of the oxidation-reduction state in the vessel wall might be an important pathogenic mechanism in atherosclerosis.

	Atherosclerosis as an Inflammatory Disease

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The view that atherosclerosis is an inflammatory disease has become increasingly prevalent in recent years.²⁵ Consequently, interest has accelerated in the mechanisms that cause localization of monocytes and T cells in the arterial wall. Emphasis has been on the expression by endothelial cells of leukocyte adhesion molecules and on chemotactic proteins and factors that facilitate the recruiting, expanding, and sustaining of the monocyte/macrophage population. Adherence of monocytes to arterial endothelium in lesion-prone areas (areas of low shear stress) was one of the first changes noted after cholesterol feeding was begun in experimental animals.²⁶ This localization was subsequently shown to be associated with the expression by the endothelial cells to which the leukocyte is attached of an adhesion molecule that was first identified as atherosclerosis-related leukocyte adhesion molecule, or athero-ELAM.²⁷ This molecule was the rabbit equivalent of vascular cell adhesion molecule-1 (VCAM-1) in humans and other species. A possible relation between VCAM expression and oxidized LDL was established when an important component of this modified lipoprotein, lysophosphatidylcholine, was shown to stimulate VCAM expression in vitro.²⁸ Subsequently, modified LDL was also shown to stimulate the chemokine, monocyte chemotactic protein-1 (MCP-1).²⁹ Modified LDL also has been shown to stimulate the production of monocyte colony stimulating factor (mCSF).³⁰ Thus, in atherosclerosis the major mechanisms for recruiting and sustaining leukocyte populations into the vessel wall have been associated with the modifications of LDL, one of the most important of which is oxidation. These data do not, however, prove a direct causal relation between oxidized LDL and the recruitment of inflammatory cells into atherosclerotic lesions. Nonetheless, the presence of oxidized LDL in human atherosclerotic lesions raises the general issue that signals emanating from abnormal oxidative metabolism in the artery might be important in eliciting the inflammatory response.

Recent evidence suggests that the molecular link between hyperlipidemia and the recruitment of inflammatory cells into the atherosclerotic arterial wall may be the metabolic stress imposed on the endothelium and the resultant excessive production of oxygen free radicals.^{31 32} Aortas from rabbits that had been fed a high cholesterol diet for several weeks produced severalfold more oxygen free radicals than did control aortas (Fig 1). Furthermore, removal of the endothelium resulted in reduction of free radical production, suggesting that the endothelium is a major source of the reactive oxygen species in this model. This oxygen free radical production had obvious functional consequences because defective endothelium-dependent relaxation in these vessels could be restored with antioxidants³³ or by decreasing free radical production by returning the animals to their normal low-cholesterol diet.³¹ In aggregate these data were consistent with the hypothesis that the abnormal redox state in the arterial wall may be a fundamental metabolic feature of atherosclerosis that is a major contributor to disordered control of vasomotor tone in coronary artery disease, as alluded to above.

View larger version (15K): [in this window] [in a new window]   Figure 1. Bar graph shows oxygen free radical production by aortas with or without endothelium (Endo) from rabbits with or without a high-cholesterol diet (Cholest-Fed). Oxygen free radical production was estimated by lucigenin chemiluminescence. Endothelium removal in a normal artery increases free radical production, suggesting that normal endothelium may serve an antioxidant role. Cholesterol feeding is associated with a severalfold increase in O2- production in intact aortas. In contrast with the normal artery, endothelium removal in aortas taken from hypercholesterolemic animals is associated with a decrease in O2- production, suggesting that hypercholesterolemia results in a striking increase in free radical production by the endothelium. Data are mean±SEM. *P<.05 for normal vessels with and without endothelium (paired t test); **P<.001 for hypercholesterolemic vs normal vessels with endothelium (unpaired t test); P<.05 for hypercholesterolemic vessels with vs without endothelium (paired t test). (From Ohara et al31 by copyright permission of The Society for Clinical Investigation.)

Recently, a relation between oxidative stress in the arterial wall (in particular, the endothelium) and the development of the inflammatory response has been clarified. The stimulation by cytokines such as interleukin-1 (IL-1) of the expression of VCAM-1 by human endothelial cells is mediated by redox-sensitive control mechanisms.³⁴ The redox-sensitive nature of this gene regulation was determined by the use of antioxidants that are active intracellularly. As shown in Figs 2 and 3, the antioxidant pyrolidine dithiocarbamate (PDTC) inhibited the IL-1–induced endothelial expression of mRNA for VCAM-1 and was as effective as a monoclonal antibody against the VCAM-1 counterligand very late antigen-4 (VLA-4) in inhibiting binding of Molt-4 cells, which express VLA-4.

View larger version (78K): [in this window] [in a new window]   Figure 2. Blots show that induction of human umbilical vein endothelial (HUVE) cell vascular cell adhesion molecule-1 (VCAM-1) mRNA by interleukin (IL)-1ß is selectively inhibited by the antioxidant pyrolidine dithiocarbamate (PDTC). After pretreatment for 30 minutes with 50 µmol/L PDTC, HUVE cells were exposed to IL-1ß (10 U/mL) in the continuous presence of 50 µmol/L PDTC. Total RNA was isolated and 20 µg size fractionated by denaturing 1.0% agarose-formaldehyde gel electrophoresis, transferred to nitrocellulose, and hybridized to either 32P-labeled human VCAM-1–specific (A), E-selectin–specific (B), or intracellular adhesion molecule-1 (ICAM-1)–specific (C) cDNA and visualized by autoradiography. Lane 1, 0 hour; lanes 2, 4, 6, and 8, IL-1ß alone for 2, 4, 8, and 24 hours, respectively; lanes 3, 5, 7, and 9, IL-1ß with PDTC for 2, 4, 8, and 24 hours, respectively. Data are consistent with a selective redox-sensitive mechanism controlling VCAM-1 mRNA expression. (From Marui et al34 by copyright permission of The Society for Clinical Investigation.)

View larger version (14K): [in this window] [in a new window]   Figure 3. Bar graphs show vascular cell adhesion molecule-1 (VCAM-1)–mediated adhesion of Molt-4 cells to tumor necrosis factor (TNF)-–activated human umbilical vein endothelial (HUVE) cells inhibited by pyrolidine dithiocarbamate (PDTC). Molt-4 cells express VLA-4, the counterligand for VCAM-1. A, HUVE cells in 48-well dishes were either pretreated or not for 1 hour with PDTC (50 µmol/L) followed by TNF- (100 U/mL) or control (CTL). After 6 hours, 51Cr-labeled Molt-4 cells were added, and binding was determined. *P<.05 by Student's t test. B, Same as in A, except TNF- was used at 500 U/mL. Anti–VCAM-1 monoclonal antibody (mAB) p3c4 was added for 15 minutes before addition of Molt-4 cells. Expression of VCAM-1 at the cell surface is inhibited by the antioxidant. (From Marui et al34 by copyright permission of The Society for Clinical Investigation.)

The inhibition of VCAM-1 expression by PDTC appears to occur at the level of gene transcription.³⁴ Constructs of the VCAM-1 gene promoter were connected to the gene encoding for the enzyme chloramphenicol acetyltransferase (CAT), which provides a readout of promoter activation. These constructs were transfected into endothelial cells for assessment of transcriptional control mechanisms. CAT activity was found to be stimulated by IL-1 and inhibited by PDTC, suggesting that a redox-sensitive mechanism controls transcription of the VCAM-1 gene. A clue to the potential identity of the protein factors controlling transcription was the presence in the VCAM-1 gene promoters of consensus binding sites for the protein nuclear factor kappa B (NFB). NFB represents a family of so-called transcription factors that are present in the cytoplasm and translocate to the nucleus and bind to gene promoters when activated.³⁵ NFB proteins were present in the nuclei of IL-1–stimulated endothelial cells, as reflected in their binding to NFB sequences from the VCAM-1 promoter.³⁴ This translocation to the nucleus was inhibited by PDTC. Oxidized LDL also stimulated VCAM-1 expression in endothelial cells by this mechanism (unpublished data, 1994). Moreover, the redox-sensitive control mechanism was specific for VCAM-1: other endothelial leukocyte adhesion molecules (eg, E-selectin and intracellular adhesion molecule-1 [ICAM-1]) were not regulated in this manner. Thus, certain details of the molecular link between hyperlipidemia and the recruitment of inflammatory cells into the arterial wall are becoming understood. The current hypothesis is that hyperlipidemia induces an oxidative stress on the endothelium that leads to the production of oxygen radical species that stimulate VCAM-1 expression, contributing to monocyte and lymphocyte recruitment.³⁶

As alluded to previously, other molecules such as mCSF and MCP-1 that are involved in the recruiting and sustaining of the monocyte/macrophage population also appear to be regulated by redox-sensitive mechanisms.³⁷ This suggests that the pathogenesis of atherosclerosis reflects in part the stimulation in the endothelial cell of a set of redox-sensitive genes by oxygen free radicals. Parenthetically and as noted, this free radical production also probably accounts for the defective endothelium-dependent vasodilation characteristic of atherosclerotic vessels. Thus, a certain mechanistic unification theory appears to be developing.³⁶

	The Effects of Hypertension on the Arterial Wall

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The pathogenesis of hypertension is a multifactorial process that involves the interaction of genetic and environmental factors. In varying degrees, abnormalities of volume regulation, enhanced vasoconstriction, and remodeling of the arterial wall (decreasing lumen diameter and increasing resistance) contribute to the development of hypertension.³⁸ Various abnormalities in ion transport have been described in subsets of hypertensive individuals and in experimental models. These generally involve changes in sodium, calcium, and/or proton fluxes or concentrations. These changes in electrolyte metabolism enhance contractile response and hypertrophy and proliferation of vascular smooth muscle cells. Growth and hypertrophy of the vessel wall in a small artery are illustrated in Fig 4. Increases in blood pressure cause ongoing adaptive responses in the microvasculature. The effects of blood pressure are also exhibited in larger arteries. In Fig 5, a renal artery shows reduplication of the internal elastic lamina with hypertrophy of the blood vessel that encroaches on the lumen. The increased growth response of vascular smooth muscle is one of the characteristics of atherosclerosis in large arteries. Thus, increased vascular smooth muscle cell growth is another common feature in the pathogenesis of both atherosclerosis and hypertension. The growth of vascular smooth muscle is controlled to an important extent by the endothelium.⁴ The normal endothelium appears to exhibit an inhibitory influence on vascular smooth muscle cell growth. Dysfunctional endothelium in either atherosclerosis or hypertension may contribute to or permit vascular smooth cell growth, which contributes to narrowing of the lumen.

View larger version (17K): [in this window] [in a new window]   Figure 4. Diagram shows effect of hypertension on smooth muscle cells. Smooth muscle cells grow either by hyperplasia (increase in number) or hypertrophy (increase in mass). In hypertensive animals, changes in smooth muscle mass in large vessels appears to be caused by hypertrophy, often with endoreplication of DNA that results in a greater-than-normal diploid content of the DNA. In arterioles, however, smooth muscle cell mass changes appear to be caused by a true increase in cell number. (From Alexander et al.39 )

View larger version (148K): [in this window] [in a new window]   Figure 5. Photomicrograph shows fibroelastic hyperplasia in a proximal renal interlobular artery from a patient with long-standing essential hypertension. As a consequence of this ongoing benign condition, there is marked reduplication (splitting) of the internal elastic lamina, marked smooth muscle hypertrophy of the media, mild medial fibrosis, and intimal thickening. (From Alexander et al.39 )

Another effect of medial thickening (whether from hypertrophy and hypertension or from atherosclerosis) is to increase the distance required for diffusion of oxygen from the lumen. A decrease in PO₂, in turn, would result in incomplete oxidation and probably lead to increased concentrations of free radicals and abnormalities of the redox state.^{40 41} This oxygen radical formation would contribute to tissue damage and lipid oxidation, with many of the implications discussed above.

There is increasing evidence that hypertension, like hyperlipidemia, induces oxidative stress in the arterial wall. It has even been suggested that superoxide anions might trigger the development of hypertension in some models, presumably by inactivating endothelium-derived nitric oxide and thus mitigating this important vasodilator mechanism.⁴² A fusion protein was developed consisting of human copper/zinc superoxide dismutase (SOD) and a C-terminal basic peptide that would provide high affinity for heparans on endothelial cells. SOD targeted to the endothelium would dismutate oxygen free radicals to H₂O₂. This SOD fusion protein bound vascular endothelial cells when injected intravenously and localized within the vessel wall, reducing blood pressure in spontaneously hypertensive rats but not normal controls (Fig 6). Blood pressure was also reduced by xanthine oxidase inhibitors. These observations suggest that oxygen free radicals may be important in the pathogenesis of hypertension in this model and that xanthine oxidase may be one potential source of the oxygen free radicals. An inferred mechanism of blood pressure elevation here would be the destruction of nitric oxide by excessive production of oxygen free radicals, although this has not been demonstrated in this model.

View larger version (18K): [in this window] [in a new window]   Figure 6. Line graph shows effect of a superoxide dismutase (SOD) fusion protein (HB-SOD) targeted to the endothelium on blood pressure of spontaneously hypertensive rats (SHR) and normal rats. Blood pressure was determined in the tail artery of conscious rats using a programmable sphygmomanometer. With rats under light ether anesthesia, either SOD (open symbols) or HB-SOD (closed symbols) was administered (25 mg/kg IV) to SHR (circles) and normal rats (squares). Data show mean±SD derived from 10 to 16 experiments. Arrow shows time of SOD or HB-SOD injection. Thus, SOD that is targeted to the arterial wall lowers blood pressure, suggesting that vascular free radical production contributes to hypertension in this model. (From Nakazono et al.42 )

Additional data in other models of hypertension support the notion that oxygen free radicals contribute to either the causes or consequences of hypertension.⁴³ Infusion of SOD in rats in which hypertension was induced by the administration of systemic norepinephrine shifted the norepinephrine–blood pressure response curves to the right. There was also improved survival in all of the SOD-treated rats, a result consistent with the possibility that oxygen free radicals produced by the arterial wall compromise vascular structural integrity in this model. These data are consistent with the possibility that this model is associated with increased production of oxygen free radicals that destroy endothelium-derived nitric oxide and contribute to hypertension. This same group has shown that acute hypertension caused by experimental acute brain injury or by pressor agents is associated with abnormalities of cerebral arterioles, including the development of endothelial lesions and increased permeability that is thought to result from enhanced production of free radicals.^{43 44 45 46 47} Similar conclusions have been reached from studies on intestinal microvascular damage in a rat model of acute angiotensin II–induced hypertension.⁴⁸

Additional evidence that hypertension induces an oxidative stress on the arterial wall comes from a rabbit suprarenal aortic coarctation model of hypertension. Here, antioxidant defense enzymes related to the generation of reduced glutathione and thiobarbituric acid–related substances (TBARS), formed when oxygen radicals interact with fatty acids, were increased in the suprarenal but not in the infrarenal aortic segment.⁴⁹

	Hypertension and Atherosclerosis May Act Together to Enhance Arterial Oxidative Stress

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The evidence reviewed here suggests that atherosclerosis and hypertension each may enhance the oxidative stress of the arterial wall. One might expect additive effects from the presence of both conditions, and indirect evidence supports this notion. In rabbits, hypertension and hyperlipidemia each enhance arterial expression of antioxidant scavenger enzymes. The presence of both conditions is an even more potent stimulus, suggesting that through a common mechanism both conditions enhance the oxidative stress of the arterial wall.⁴¹ Additional provocative evidence supporting the concept that hypertension and atherosclerosis have certain common physiological mechanisms comes from observations in cholesterol-fed monkeys; here, hypertension sustained coronary artery plaque progression despite the return of cholesterol levels toward normal with dietary manipulation.⁵⁰

Chobanian⁵¹ has called attention to and summarized similarities in the effects of hypertension and atherosclerosis on the arterial wall. The argument presented above suggests that oxidative stress is a manifestation common to both conditions. The mechanistic data showing that monocyte recruitment mechanisms involve redox-sensitive steps have been previously summarized and would lead one to predict that hypertension per se, even in the absence of the metabolic stress of hyperlipidemia, might be associated with increased recruitment of mononuclear cells into the arterial wall. In fact, this appears to be the case. Hypertension in animal models is associated with leukocyte adhesion, macrophage accumulation, smooth muscle cell migration and proliferation, and intimal thickening.^{51 52 53} Lipid accumulation in foam cells and formation of atherosclerotic plaque are generally not observed if plasma lipoproteins are low.⁵⁴ Thus, one reason that hypertension facilitates the development and progression of atherosclerosis may be that it oxidatively stresses or injures the endothelium, resulting in activation of redox-sensitive mechanisms that recruit mononuclear leukocytes into the arterial wall.

	Summary and Conclusions

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Hypertension and hyperlipidemia exert many similar effects on the arterial wall. The increase in oxidative stress, a mechanism common to both conditions, may activate genes involved in generating an inflammatory response that, in the presence of hyperlipidemia, leads to the formation of atherosclerotic plaque (see Fig 7). There is a great deal of interest in the use of antioxidants in the treatment of atherosclerosis. The possibility that members of this class of compounds might also ameliorate hypertensive vascular injury deserves further investigation.

View larger version (24K): [in this window] [in a new window]   Figure 7. Flow chart shows mechanism of synergism of hypertension and hyperlipidemia in the pathogenesis of atherosclerosis. When hypertension accompanies hyperlipidemia, the two act together to trigger a cascade. Increased production of oxygen free radicals leads to increased transcription of redox-sensitive genes, which increases expression of vascular cell adhesion molecule-1 (VCAM-1) by the endothelium, resulting in increased recruitment of monocytes. Both hypertension and hyperlipidemia cause oxidative stress and oxygen free radical production by the arterial wall. By activating redox-sensitive transcriptional control mechanisms in the endothelium, a set of genes controlling monocyte recruitment into the arterial wall is activated. Atherosclerosis and foam cell formation occur only in the presence of hyperlipidemia. A synergistic reaction between hypertension and hyperlipidemia, causing or enhancing atherosclerosis, may occur because both states are associated with a common causal mechanism: induction of alterations in vascular redox state. mCSF indicates monocyte colony stimulating factor; MCP-1, monocyte chemotactic protein-1.

	Acknowledgments

 
This work was supported in part by Program Project Grant No. PO1HL-48667 in Vascular Biology from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Md. The author also wishes to thank Kate W. Harris for invaluable assistance in the preparation of this manuscript.

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