期刊
HYPERTENSION
卷 52, 期 3, 页码 556-562出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.108.115287
关键词
angiotensin; hypertension; cardiac remodeling; LOX-1; oxidative stress
资金
- Department of Veterans Affairs
- American Heart Association
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Ministry of Health, Labor, and Welfare of Japan
- National Institute of Biomedical Innovation, Japan
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.
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