Modulation of Angiotensin II–Mediated Hypertension and Cardiac Remodeling by Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Deletion

Abstract

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...

Lectin-like Oxidized Low-density Lipoprotein Receptor-1 (LOX-1) and Cardiac Fibroblast Growth

“…After 4 weeks of continuous infusion, there was significant cardiac fibroblast growth (discoidin domain receptor 2 immunopositivity) and collagen accumulation (Picro-Sirius staining) in between cardiomyocytes and in the perivascular regions throughout the hearts of WT mice ( Figure 5B). In keeping with previous observations, 15 there was a significant decrease in collagen in the accumulation LOX-1 KO mice despite similar duration of Ang II administration. The number of fibroblasts in the heart sections was much fewer and collagen deposition much less in the LOX-1 KO mice hearts than in WT mice hearts (P<0.01).…”

“…However, the LOX-1-Ang II interaction described here seems to be unique, and this relationship is not seen in norepinephrine-induced hypertension. 15 In summary, we provide strong evidence that LOX-1 is involved in the maintenance of fibroblast cytoskeleton. LOX-1 also seems important in fibroblast division and growth, resulting in collagen formation.…”

“…The model of LOX-1 deletion has been extensively used in models of atherogenesis, 34 myocardial ischemia, 9,10 and hypertension. 15 In all these models, LOX-1 deletion was shown to reduce ROS generation, NF-κB activity, and collagen deposition. The results of the in vivo studies are in concert with the in vitro data of limited fibroblast potential in the absence of LOX-1.…”

Serum sLOX-1 levels are associated with the presence and severity of angiographic coronary artery disease in patients with metabolic syndrome

“…Moreover, Taye et al demonstrated that hyperglycemia-induced generation of reactive oxygen species (ROS) contributed to LOX-1 upregulation in human endothelial cells [23]. Hu et al reported that angiotensin II mediated hypertension upregulated the expression of LOX-1 [24]. Recent studies have also found that circulating levels of sLOX-1 are signi cantly increased in metabolic disorders, including obesity [11] and type 2 DM [12], and are positively correlated with reduction in body weight [13].…”

Excitement of Clinical Investigation

“…To my way of thinking, there is no better example of such an article to fulfill these criteria than "Modulation of Angiotensin II-Mediated Hypertension and Cardiac Remodeling by Lectin-Like, Oxidized Low-Density Lipoprotein Receptor-1 Deletion" by Hu et al 1 Inherent in this commentary are its key words: angiotensin II, cardiac remodeling, and lectinlike, oxidized low-density lipoprotein receptor-1 (LOX-1) deletion. Moreover, central to its thesis are the concept and mechanisms of cardiovascular "remodeling.…”