Differential effects of AT1 receptor and Ca2+ channel blockade on atherosclerosis, inflammatory gene expression, and production of reactive oxygen species

Doran, Derek E.; Weiss, Daiana; Zhang, Yong; Griendling, Kathy K.; Taylor, W. Robert

doi:10.1016/j.atherosclerosis.2006.11.030

Cited by 43 publications

(31 citation statements)

References 55 publications

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“…For example, while both AngII and norepinephrine increased blood pressure to the same extent in apoE -/-mice, only AngII accelerated atherosclerosis (10). Furthermore, the profound decreases in atherosclerotic lesion size during administration of AT1 receptor antagonists were not observed with either hydralazine or amlodipine when administered at doses resulting in equivalent reductions in systolic blood pressure (7,41). Thus, while increased systolic blood pressure is frequently associated with atherosclerosis, the stimulus for the hypertension appears to be the major determinant of atherogenesis rather than pressure per se (42).…”

Section: Figurementioning

confidence: 94%

Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice

Lü¹,

Rateri²,

Feldman³

et al. 2008

J. Clin. Invest.

142

186

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The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr -/-) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr -/-mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice.

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Section: Figurementioning

confidence: 94%

Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice

Lü¹,

Rateri²,

Feldman³

et al. 2008

J. Clin. Invest.

142

186

View full text Add to dashboard Cite

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“…Also, candesartan, but not amlodipine, inhibited aortic expression of inflammatory genes and production of reactive oxygen species. 127 The ARB valsartan improved vascular compliance, but not flow-mediated dilation, in healthy normotensive elderly individuals 128 and losartan reduced monocyte chemoattractant protein-1 expression in the aortic tissues of 2K1C hypertensive rats. 129 Combinations of 2 drugs may also prove useful.…”

Section: Therapeutic Potentialmentioning

confidence: 99%

Smoking and Aortic Diseases

Kakafika

Mikhailidis

2007

Circ J

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Cigarette smoking is a major cause of cardiovascular disease (CVD) and is responsible for approximately 11% of the annual total CVD deaths in the United States. 1 Smoking acts synergistically with other vascular risk factors (eg, hypertension, dyslipidaemia and diabetes) to increase vascular morbidity and mortality. 2 However, smoking has a variable magnitude of increased risk for different vascular diseases: the risk is highest for peripheral arterial disease and aortic aneurysm, and is lowest for coronary artery and cerebrovascular diseases. 2 These effects are thought to reverse after smoking cessation. The constituents of cigarette smoke with the major contribution to pathogenesis of vascular disease are nicotine, carbon monoxide, oxidant gases and polycyclic aromatic hydrocarbons. 2 Nonsmokers who are exposed to "secondhand" smoke experience on average a 30% excess risk of ischemic heart disease and nonfatal myocardial infarction. 3 Secondhand smoke exposure has been shown to activate platelets and to produce endothelial dysfunction, in both experimental animals and humans. 3 The mechanisms by which smoking causes acute cardiovascular events include endothelial dysfunction, thrombosis and inflammation.Endothelial dysfunction is an initiating event in atherogenesis, as well as a major factor in causing acute cardiovascular events. Cigarette smoking impairs flow-mediated endothelium-dependent peripheral arterial vasodilatation, an effect that is, at least partly, reversible after smoking Circulation Journal Vol.71, August 2007 cessation. 4 Smokers without atherosclerosis have coronary vasoconstrictor responses to acetylcholine that, in the presence of normal endothelium, produce vasodilatation. 5 Indeed, the oxidant chemicals of smoke degrade nitric oxide (NO) and reduce NO release, with subsequent impairment of vascular dilation and platelet function. 2 Smokers have lower than normal levels of antioxidant vitamins, reflecting their consumption in response to ongoing oxidant stress. 6 In addition, nicotine itself alters the structural and functional characteristics of vascular smooth muscle cells (VSMC) and endothelial cells. 7,8 Experimental data show that human aortic endothelial cells undergo apoptotic changes when they are exposed to cigarette smoke extracts. 9 This process may be prevented by pre-activation of NO synthase by Larginine. 9,10 Furthermore, smoking causes an increase in vascular superoxide production, which results in decreased NO bioactivity and concomitantly increases production of vasoconstrictor eicosanoids. 11 Cigarette smoke extracts, but not nicotine, also inhibit prostacyclin (PGI2: a vasodilator and inhibitor of platelet aggregation) synthesis in human, rabbit and rat vascular tissue. 12 Smoking-mediated endothelial dysfunction also results in reduced secretion of tissue plasminogen activator (tPA) 13 and increased secretion of plasminogen activator inhibitor (PAI)-1, 1 which results in impaired fibrinolysis. This acts in concert with the increased levels of tissue factor and fibrin...

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“…We posited that since both ANG II and BMP-4 stimulate ROS release from the Nox1-dependent NADPH oxidase leading to inflammation (11,47,51), either or both might play a causal role in the vascular inflammation found in db/db mice. We found that although both inhibitors block superoxide production and have similar effects on inflammatory gene expression, noggin reduces glycemia, whereas valsartan reduces blood pressure in diabetic mice.…”

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confidence: 99%