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 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.
Hu
Changping
C
Department of Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.
Dandapat
Abhijit
A
Sun
Liuqin
L
Marwali
Muhammad R
MR
Inoue
Nobutaka
N
Sugawara
Fumiaki
F
Inoue
Kazuhiko
K
Kawase
Yosuke
Y
Jishage
Kou-ichi
K
Suzuki
Hiroshi
H
Hermonat
Paul L
PL
Sawamura
Tatsuya
T
Mehta
Jawahar L
JL
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000235:genetics* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000502:physiology*
D044140:Receptor, Angiotensin, Type 1; D051127:Scavenger Receptors, Class E; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D009638:Norepinephrine