Objective-Vascular endothelial growth factor (VEGF), a key angiogenic growth factor, stimulates angiogenesis. Low levels of reactive oxygen species (ROS) function as signaling molecules for angiogenesis. We postulated that low concentrations of oxLDL might induce low levels of ROS and initiate angiogenesis. Methods and Results-An in vitro model of tube formation from human coronary artery endothelial cells (HCAECs) was used.oxLDL (0.1, 1, 2, 5 g/mL) induced VEGF expression and enhanced tube formation. oxLDL-mediated VEGF expression and tube formation were suppressed by a specific blocking anti-LOX-1 antibody. Anti-LOX-1 antibody also reduced oxLDL-induced increase in the expression of NADPH oxidase (gp91 phox and p47 phox subunits) and subsequent intracellular ROS generation, phosphorylation of p38 as well as p44/42MAPK, and NF-B p65 expression. gp91 phox siRNA had a similar effect. The expression of VEGF and NF-B p65 induced by oxLDL was also inhibited by the specific extracellular signal-regulated kinase (ERK) 1/2 inhibitor U0126 and the p38 MAPK inhibitor SB203580. Importantly, the NADPH oxidase inhibitor apocynin, gp91 phox siRNA, U0126, and SB203580 all reduced tube formation in response to oxLDL. Conclusions-These
Abstract-Angiotensin II via type 1 receptor activation upregulates the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and LOX-1 activation, in turn, upregulates angiotensin II type 1 receptor expression. We postulated that interruption of this positive feedback loop might attenuate the genesis of angiotensin II-induced hypertension and subsequent cardiac remodeling. To examine this postulate, LOX-1 knockout and wild-type mice were infused with angiotensin II or norepinephrine (control for angiotensin II) for 4 weeks. Angiotensin II-, but not norepinephrine-, induced hypertension was attenuated in LOX-1 knockout mice. Angiotensin II-induced cardiac remodeling was also attenuated in LOX-1 knockout mice. Importantly, angiotensin II type 1 receptor expression was reduced, and the expression and activity of endothelial NO synthase were preserved in the tissues of LOX-1 knockout mice given angiotensin II. Reactive oxygen species generation, nicotinamide-adenine dinucleotide phosphate oxidase expression, and phosphorylation of p38 and p44/42 mitogen-activated protein kinases were also much less pronounced in the LOX-1 knockout mice given angiotensin II. These alterations in biochemical and structural abnormalities were associated with preservation of cardiac hemodynamics in the LOX-1 knockout mice. To confirm that fibroblast function is modulated in the absence of LOX-1, cardiac fibroblasts from wild-type and LOX-1 knockout mice were treated with angiotensin II. Indeed, LOX-1 knockout mice cardiac fibroblasts revealed an attenuated profibrotic response on treatment with angiotensin II. These observations provide strong evidence that LOX-1 is a key modulator of the development of angiotensin II-induced hypertension and subsequent cardiac remodeling. (Hypertension. 2008;52:556-562.)Key Words: angiotensin Ⅲ hypertension Ⅲ cardiac remodeling Ⅲ LOX-1 Ⅲ oxidative stress C ardiac remodeling is initially an adaptive response to several forms of cardiac stress states, such as hypertension. Sustained remodeling results in heart failure and is a powerful independent risk factor for cardiac morbidity and mortality. 1 Therefore, identification of the molecular mechanisms involved in cardiac remodeling is an important challenge for the cardiovascular biologists.The renin-angiotensin system and its effector hormone, angiotensin II (Ang II), have well-known endocrine properties that contribute to cardiac remodeling and heart failure. Previous studies have shown that Ang II via type 1 receptor (AT1R) activation stimulates the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). 2 In turn, activation of LOX-1 upregulates AT1R expression. 3 Activation of both AT1R and LOX-1 induces a state of oxidative stress. 4 In addition, activation of both AT1R and LOX-1 enhances the growth of cardiac fibroblasts and promotes collagen synthesis. 5,6 Although LOX-1 mRNA expression is minimal in normal arterial tissues, it is markedly upregulated in vascular tissues of spontaneously hypertensive...
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