A Chemical Chaperone Attenuates Pressure-Overload Induced Cardiac Hypertrophy by Reducing ER Stress

Abstract

Previously, it was reported that the endoplasmic reticulum (ER) stress could be involved in the pathological hypertrophy and the antagonism of angiotensin II type receptors could prevent ER chaperone expression and apoptosis (Ken-ichiro Okada et al. Circulation. 2004). We investigated whether the direct alleviation of ER stress by treating with a chemical chaperone could attenuate the hypertrophy. Transverse aortic constriction (TAC) was applied to induce pressure-overload hypertrophy in mice. The chemical chaperone was orally administered in the TAC operated mice (100mg/kg, daily). One week later, the heart was harvested for molecular study. The chemical chaperone/TAC group showed a reduction of ER stress, attenuation of hypertrophy and elimination of fibrosis compared with water/TAC group. We found down-regulation of GRP78/94, 10% attenuation of HW/BW ratio as well as the down-regulation of the hypertrophic marker genes compared with water/TAC group. The expression of collagen 1α1, 1α2, 3α1, TGF-β1, β3 and TGF-βR2, and the phospho-Smad2 responsible for the fibrosis were completely down-regulated in the chemical chaperone/TAC group compared with water/TAC group. Our results suggest that overload of protein in ER raises the unfolded protein response (UPR) in TAC model. The UPR could activate the MAP kinase which participated in the TGF-β up-regulation. In turn, TGF-β could aggravate the fibrosis by SMAD pathway. But the chemical chaperone helps to relieve the ER stress in pathological hypertrophy. As a result, the hypertrophy and the fibrosis could be reduced by down-regulation of MAPK - TGF-β - SMAD pathway. (Supported by Korea MEST NRF Grant (20110002144), the 2011 GIST System Biology Infrastructure Establishment Grant and KISTI-KREONET).