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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...