Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion

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 atte...

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Published in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 2008-09, Vol.52 (3), p.556-562
Main Authors: Hu, Changping, Dandapat, Abhijit, Sun, Liuqin, Marwali, Muhammad R, Inoue, Nobutaka, Sugawara, Fumiaki, Inoue, Kazuhiko, Kawase, Yosuke, Jishage, Kou-ichi, Suzuki, Hiroshi, Hermonat, Paul L, Sawamura, Tatsuya, Mehta, Jawahar L
Format: Article
Language:English
Subjects:
Angiotensin II - pharmacology
Animals
Blood Pressure - drug effects
Cells, Cultured
Fibroblasts - cytology
Fibroblasts - physiology
Gene Deletion
Gene Expression - drug effects
Gene Expression - physiology
Hypertension - metabolism
Hypertension - physiopathology
Mice
Mice, Knockout
Myocardium - cytology
Myocardium - metabolism
Nitric Oxide Synthase Type II - genetics
Nitric Oxide Synthase Type III
Norepinephrine - metabolism
Norepinephrine - pharmacology
Oxidative Stress - drug effects
Oxidative Stress - physiology
Receptor, Angiotensin, Type 1 - genetics
Scavenger Receptors, Class E - genetics
Scavenger Receptors, Class E - metabolism
Vasoconstrictor Agents - pharmacology
Ventricular Remodeling - physiology
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Summary: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.
ISSN:0194-911X
1524-4563
DOI:10.1161/hypertensionaha.108.115287