on July 21, 2008
Published online before print July 21, 2008, doi: 10.1161/HYPERTENSIONAHA.108.115287
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Submitted on April 22, 2008
From the Department of Medicine and Physiology and Biophysics (C.H., A.D., L.S., M.R.M., P.L.H., T.S., J.L.M.), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock; Department of Pharmacology (C.H.), School of Pharmaceutical Sciences, Central South University, Changsha, China; Department of Ophthalmology (L.S.), Heping Hospital, Changzhi Medical College, Changzhi, China; Department of Vascular Physiology (N.I., F.S., K.I., T.S.), National Cardiovascular Center Research Institute, Osaka, Japan; Chugai Research Institute for Medical Science (Y.K., K-i.J.), Shizuoka, Japan; and Obihiro University of Agriculture and Veterinary Medicine (H.S.), Hokkaido, Japan. * To whom correspondence should be addressed. E-mail: MehtaJL{at}uams.edu.
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.
Revised on May 12, 2008
Modulation of Angiotensin II–Mediated Hypertension and Cardiac Remodeling by Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Deletion
Changping Hu;
Key words: angiotensin • hypertension • cardiac remodeling • LOX-1 • oxidative stress
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