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.

Lipoproteins: A Source of Cardiac Lipids

“…Besides chronic ischemia, LOX1 may also be detrimental for cardiac damage that occurs in ischemia-reperfusion. Specifi cally, LOX-1 increased in rat cardiomyocytes following ischemia-reperfusion, while administration of anti-LOX-1 antibody reduced myocardial infarction size [ 120 ] and LOX-1 genetic deletion reduced ischemia-driven collagen accumulation [ 121 ]. Therefore, LOX-1 appears to be involved in ischemic heart failure as it activates stress signaling kinases, such as JNK and ERK [ 112 ].…”

“…Abrogation of LOX-1 in an animal model of chronic ischemia reduced infarct size, improved cardiac hemodynamics, prevented cardiac remodeling and fi brosis and improved survival [ 121 ]. Besides chronic ischemia, LOX1 may also be detrimental for cardiac damage that occurs in ischemia-reperfusion.…”

Lectin-like Oxidized Low-density Lipoprotein Receptor-1 (LOX-1) and Cardiac Fibroblast Growth

“…The homozygous LOX-1 KO mice were developed and backcrossed eight times with C57BL/6 strain to replace the genetic background [8,11]. This investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No.…”

“…In recent studies, LOX-1 deletion was shown to limit cardiac hypertrophy and the remodeling process in mice subjected to sustained hypertension or myocardial ischemia. [8][9][10] Part of the decrease in cardiac remodeling with LOX-1 deletion seems to be related to reduction in fibrosis in the heart. 8 In view of markedly reduced collagen deposition and fibrosis in the LOX-1 knockout (KO) mice hearts, we posited that LOX-1 may modulate fibroblast growth, a key factor for cardiac fibrosis.…”

Modified Low-Density Lipoprot Eins in Di Abetes Mellitus Type 2

“…Кроме того, есть данные, что мЛПНП сами по себе могут вступать во взаимодей-ствие и активировать СРБ [19]. Важно отметить, что, кроме активации системы комплемента, LOX-1 [20] и СРБ [21] могут сами непосредственно участвовать в фиброзе миокарда. Таким образом, повышение уров-ня мЛПНП запускает многофакторные процессы, которые в конечном итоге могут приводить к фиброзу миокарда.…”