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LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse

Gene Therapy volume 19, pages 522–531 (2012)Cite this article

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.

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Abbreviations

ADAM:

a disintegrin and metalloproteinase

Ang II:

angiotensin II

AT1R:

angiotensin II type 1 receptor

AT2R:

angiotensin II type 2 receptor

KO:

knockout

LCA:

left coronary artery

LOX-1:

lectin-like oxidized LDL receptor-1

LV:

left ventricle

LVIDd:

left ventricular internal diameter in diastole

LVIDs:

left ventricular internal diameter in systole

MAPK:

mitogen-activated protein kinase

MDA:

malondialdehyde

MI:

myocardial infarct

MMP:

matrix metalloproteinase

NADPH:

nicotinamide adenine dinucleotide phosphate

NF-κB:

nuclear factor-kappaB

ROS:

reactive oxygen species

SAPK/JNK:

stress-activated protein kinase/c-Jun NH2-terminal kinase

TBARS:

thiobarbituric acid-reactive substances

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Acknowledgements

This study was supported in part by funds from the Department of Veterans Affairs.

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Author notes

  1. J Lu and X Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Central Arkansas Veterans Healthcare System and Departments of Internal Medicine, Division of Cardiovascular Medicine, Pathology and Pharmacology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    J Lu, X Wang, W Wang, H Muniyappa, C Hu, S Mitra, B Long, K Das & J L Mehta

  2. Department of Emergency Medicine, Renmin Hospital of Wuhan University, Wuhan, China

    J Lu

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Lu, J., Wang, X., Wang, W. et al. LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse. Gene Ther 19, 522–531 (2012). https://doi.org/10.1038/gt.2011.133

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