title: LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse.
abstract: We hypothesized that lectin-like oxidized LDL receptor-1 (LOX-1) deletion may inhibit oxidative stress signals, reduce collagen accumulation and attenuate cardiac remodeling after chronic ischemia. Activation of LOX-1 plays a significant role in the development of inflammation, apoptosis and collagen signals during acute ischemia. Wild-type and LOX-1 knockout (KO) mice were subjected to occlusion of left coronary artery for 3 weeks. Markers of cardiac hypertrophy, fibrosis-related signals (collagen IV, collagen-1 and fibronectin) and oxidant load (nicotinamide adenine dinucleotide phosphate oxidase expression, activity of mitogen-activated protein kinases and left ventricular (LV) tissue thiobarbituric acid reactive substances) were analyzed. In in vitro experiments, HL-1 cardiomyocytes were transfected with angiotensin II (Ang II) type 1 receptor (AT1R) or type 2 receptor (AT2R) genes to determine their role in the cardiomyocyte hypertrophy. LOX-1 KO mice had 25% improvement in survival over the 3-week period of chronic ischemia. LOX-1 deletion reduced collagen deposition and cardiomyocyte hypertrophy (∼75%) in association with a decrease in oxidant load and AT1R upregulation (all P<0.05). The LOX-1 KO mice hearts exhibited a disintegrin and metalloproteinase 10 (ADAM10) and a disintegrin and metalloproteinase 17 (ADAM17) expression and matrix metalloproteinase 2 activity, and increased AT2R expression (P<0.05). Attenuation of cardiac remodeling was associated with improved cardiac hemodynamics (LV ±dp/dt and cardiac ejection fraction). In vitro studies showed that it is AT1R, and not AT2R overexpression that induces cardiomyocyte hypertrophy. We demonstrate for the first time that LOX-1 deletion reduces oxidative stress and related intracellular signaling, which leads to attenuation of the positive feedback loop involving AT1R and LOX-1. This results in reduced chronic cardiac remodeling.
authors.affiliation: Central Arkansas Veterans Healthcare System, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Muniyappa
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Mitra
authors.forename: B
authors.initials: B
authors.lastname: Long
authors.forename: K
authors.initials: K
authors.lastname: Das
authors.forename: J L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D003094:Collagen / Q000378:metabolism*; D054059:Coronary Occlusion / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000235:genetics*; D018384:Oxidative Stress; D051127:Scavenger Receptors, Class E / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E; D003094:Collagen