title: Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion.
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.
authors.affiliation: Department of Medicine and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.
authors.forename: Changping
authors.initials: C
authors.lastname: Hu
authors.forename: Abhijit
authors.initials: A
authors.lastname: Dandapat
authors.forename: Liuqin
authors.initials: L
authors.lastname: Sun
authors.forename: Muhammad R
authors.initials: MR
authors.lastname: Marwali
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Inoue
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sugawara
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Inoue
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kawase
authors.forename: Kou-ichi
authors.initials: K
authors.lastname: Jishage
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Paul L
authors.initials: PL
authors.lastname: Hermonat
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: 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*
chemical_list: 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