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

Abstract

SummaryHypertension‐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.

Relative Contributions of Matrix and Myocytes to Biaxial Mechanics of the Right Ventricle in Pulmonary Arterial Hypertension

“…Whereas banding results in a sudden increase in RV afterload, RV systolic pressures take approximately three weeks to increase in the monocrotaline and SuHx rat models of PAH. In the rat, a sudden increase in aortic pressure in the transverse aortic constriction model of left-ventricular hypertrophy is associated with more pronounced chamber remodeling than the more gradual spontaneously hypertensive rat [20]. Although most RV hemodynamic measurements were not different between rats 5 and 6 weeks after SuHx as used here, 4 weeks after monocrotaline [5], and 3 weeks after PA banding [8], one exception was mean RV end-diastolic volume.…”

Heat‐shock transcription factor 1 is critically involved in the ischaemia‐induced cardiac hypertrophy via JAK2/STAT3 pathway

“…Primary cultures of neonatal rat cardiac myocytes were prepared as described previously . Briefly, 1‐ to 2‐day‐old Sprague Dawley rats were killed by swift decapitation and their hearts were immediately removed under aseptic conditions and placed in ice‐cold sterile PBS (calcium‐ and magnesium‐free).…”

“…Mice were anesthetized by inhalation of 2% isoflurane. Transthoracic echocardiographic analysis was performed using an animal‐specific instrument (VisualSonics Vevo770, VisualSonics Inc., Canada) as previously described . Mice were anesthetized and M‐mode images of the left ventricle (LV) were recorded.…”

“…Haemodynamic assessment was performed by a 1.4 F pressure catheter (SPR 671, Millar Instruments) inserted into the aorta and LV through the right common carotid artery after mice were anesthetized by inhalation of 2% isoflurane . The transducer was connected to Powerlab system (AD Instruments, Castle Hill, Australia).…”

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

“…Recently, VCP has been found to play an essential role in mitochondrial function, including mitochondrial respiration, ATP production and mPTP opening. Overexpression of the VCP protects cardiomyocyte against stimulated death and reduces the I/R induced infarct size in the heart [ 13 , 90 , 91 , 92 ]. Notably, the most recent study found that VCP protects the heart from the stress by preventing excessive Ca 2+ overload through inhibiting Ca 2+ uptake [ 13 ].…”