Research Article: The valosin‐containing protein is a novel repressor of cardiomyocyte hypertrophy induced by pressure overload

Date Published: August 11, 2017

Publisher: John Wiley and Sons Inc.

Author(s): Ning Zhou, Ben Ma, Shaunrick Stoll, Tristan T. Hays, Hongyu Qiu.

http://doi.org/10.1111/acel.12653

Abstract

Hypertension‐induced left ventricular hypertrophy (LVH) is an independent risk factor for heart failure. Regression of LVH has emerged as a major goal in the treatment of hypertensive patients. Here, we tested our hypothesis that the valosin‐containing protein (VCP), an ATPase associate protein, is a novel repressor of cardiomyocyte hypertrophy under the pressure overload stress. Left ventricular hypertrophy (LVH) was determined by echocardiography in 4‐month male spontaneously hypertensive rats (SHRs) vs. age‐matched normotensive Wistar Kyoto (WKY) rats. VCP expression was found to be significantly downregulated in the left ventricle (LV) tissues from SHRs vs. WKY rats. Pressure overload was induced by transverse aortic constriction (TAC) in wild‐type (WT) mice. At the end of 2 weeks, mice with TAC developed significant LVH whereas the cardiac function remained unchanged. A significant reduction of VCP at both the mRNA and protein levels in hypertrophic LV tissue was found in TAC WT mice compared to sham controls. Valosin‐containing protein VCP expression was also observed to be time‐ and dose‐dependently reduced in vitro in isolated neonatal rat cardiomyocytes upon the treatment of angiotensin II. Conversely, transgenic (TG) mice with cardiac‐specific overexpression of VCP showed a significant repression in TAC‐induced LVH vs. litter‐matched WT controls upon 2‐week TAC. TAC‐induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling observed in WT mice LVs was also significantly blunted in VCP TG mice. In conclusion, VCP acts as a novel repressor that is able to prevent cardiomyocyte hypertrophy from pressure overload by modulating the mTORC1 signaling pathway.

Partial Text

Age is a well‐known risk factor for hypertension (Sun, 2015; Niiranen et al., 2017). Cardiovascular outcomes are positively and independently associated with elevated blood pressure in old individuals, which eventually results in heart failure, renal failure, or stroke and leads to a major source of mortality. Hypertensive heart disease (HHD) is characterized by left ventricular hypertrophy (LVH), cardiac dysfunction, and coronary artery flow abnormalities (Weber, 2001; Diez & Frohlich, 2010). It has been established that LVH is not only a hallmark of HHD but also a powerful independent predictor of cardiovascular morbidity and mortality (Nielsen et al., 2015; Soliman et al., 2015). Additionally, regression of LVH reduced cardiovascular complications in patients with hypertension (Soliman et al., 2015), and thus has emerged as a major goal of the antihypertensive treatments. It has been shown in patients with essential hypertension that, despite similar peripheral blood pressure control, each class of available antihypertensive drugs has different efficacies in reducing LVH (Schmieder et al., 1996). These different classes of drugs are hypothesized to have potential effects ‘beyond blood pressure control’ and likely account for the drug’s differing effects upon cardiovascular outcomes (Staessen et al., 2003). Most of the antihypertensive agents that have antihypertrophic effects target the outside‐in signaling of cardiac cells, but their effectiveness seems limited. Thus, potential novel therapeutic interventions could be greatly beneficial if they are able to directly target the myocardium itself. Identification of new mediators responsible primarily for cardiomyocyte hypertrophy is critical for the development of effective drug targets.

An increase in blood pressure (BP) has long been considered an inevitable consequence of aging, leading to cardiac complications in a high proportion of the elderly (Borghi & Tartagni, 2012). Although the long‐held view has been that LVH in response to pressure overload is an adaptive response required to sustain cardiac function, this conception has been challenged by evidence that hypertension‐induced LVH is consistently associated with cardiovascular morbidity and mortality (Bernardo et al., 2010; Frohlich et al., 2011). Accumulating evidence from studies in patients and animal models suggested that cardiac hypertrophy induced by chronic pressure overload is not a compensatory but rather a maladaptive process (Bernardo et al., 2010; Frohlich et al., 2011). LVH is not only a predictor but also a mediator of cardiovascular events such as stroke and myocardial infarction, thereby predisposing patients to arrhythmias and heart failure (Drazner, 2011). Therefore, prevention of LVH is considered as a major goal in the treatment of HHD (Diez et al., 2001; Frohlich et al., 2011; Moreno et al., 2017). The present study not only demonstrated that the downregulation of VCP is associated with the development of pressure overload‐induced cardiac hypertrophy, but also that that the overexpression of VCP is able to selectively repress the pathological cardiac hypertrophy without affecting the physiological function of the heart. These findings lead to a new therapeutic strategy for pressure overload‐induced cardiac pathogenesis by manipulating VCP or by targeting VCP mediated signaling, which is directly relevant to the condition of chronic hypertension in patients, particular in old individuals.

This work is supported by a grant 1R01 HL115195‐01 from NIH/NHLBI (Hongyu Qiu) and the National Natural Science Fund of China (81100087, 81570261, Ning Zhou).

None.

Hongyu Qiu conceived and designed the study. Ning Zhou performed the experiments and finished the manuscript. Ben Ma, Shaunrick Stoll, and Tristan Hays helped analyzing experimental results. All authors read and approved the manuscript.

 

Source:

http://doi.org/10.1111/acel.12653

 

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