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Hypertension. 2013 Jun;61(6):1184-92. doi: 10.1161/HYPERTENSIONAHA.111.00947. Epub 2013 Mar 25.

Cathepsin K knockout alleviates pressure overload-induced cardiac hypertrophy.

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1
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, 1000 E University Ave, Laramie, WY 82071, USA.

Abstract

Evidence from human and animal studies has documented elevated levels of lysosomal cysteine protease cathepsin K in failing hearts. Here, we hypothesized that ablation of cathepsin K mitigates pressure overload-induced cardiac hypertrophy. Cathepsin K knockout mice and their wild-type littermates were subjected to abdominal aortic constriction, resulting in cardiac remodeling (heart weight, cardiomyocyte size, left ventricular wall thickness, and end diastolic and end systolic dimensions) and decreased fractional shortening, the effects of which were significantly attenuated or ablated by cathepsin K knockout. Pressure overload dampened cardiomyocyte contractile function along with decreased resting Ca2+ levels and delayed Ca2+ clearance, which were partly resolved by cathepsin K knockout. Cardiac mammalian target of rapamycin and extracellular signal-regulated kinases (ERK) signaling cascades were upregulated by pressure overload, the effects of which were attenuated by cathepsin K knockout. In cultured H9c2 myoblast cells, silencing of cathepsin K blunted, whereas cathepsin K transfection mimicked phenylephrine-induced hypertrophic response, along with elevated phosphorylation of mammalian target of rapamycin and ERK. In addition, cathepsin K protein levels were markedly elevated in human hearts of end-stage dilated cardiomyopathy. Collectively, our data suggest that cathepsin K ablation mitigates pressure overload-induced hypertrophy, possibly via inhibition of the mammalian target of rapamycin and ERK pathways.

KEYWORDS:

cardiac hypertrophy; cathepsin K; contractile function; mammalian target of rapamycin

PMID:
23529168
PMCID:
PMC3929275
DOI:
10.1161/HYPERTENSIONAHA.111.00947
[Indexed for MEDLINE]
Free PMC Article
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