Cardiomyocyte-GSK-3? promotes mPTP opening and heart failure in mice with chronic pressure overload.

ABSTRACT: Chronic pressure-overload (PO)- induced cardiomyopathy is one of the leading causes of left ventricular (LV) remodeling and heart failure. The role of the ? isoform of glycogen synthase kinase-3 (GSK-3?) in PO-induced cardiac remodeling is unclear and its downstream molecular targets are largely unknown. To investigate the potential roles of GSK-3?, cardiomyocyte-specific GSK-3? conditional knockout (cKO) and control mice underwent trans-aortic constriction (TAC) or sham surgeries. Cardiac function in the cKOs and littermate controls declined equally up to 2?weeks of TAC. At 4?week, cKO animals retained concentric LV remodeling and showed significantly less decline in contractile function both at systole and diastole, vs. controls which remained same until the end of the study (6?wk). Histological analysis confirmed preservation of LV chamber and protection against TAC-induced cellular hypertrophy in the cKO. Consistent with attenuated hypertrophy, significantly lower level of cardiomyocyte apoptosis was observed in the cKO. Mechanistically, GSK-3? was found to regulate mitochondrial permeability transition pore (mPTP) opening and GSK-3?-deficient mitochondria showed delayed mPTP opening in response to Ca2+ overload. Consistently, overexpression of GSK-3? in cardiomyocytes resulted in elevated Bax expression, increased apoptosis, as well as a reduction of maximum respiration capacity and cell viability. Taken together, we show for the first time that GSK-3? regulates mPTP opening under pathological conditions, likely through Bax overexpression. Genetic ablation of cardiomyocyte GSK-3? protects against chronic PO-induced cardiomyopathy and adverse LV remodeling, and preserves contractile function. Selective inhibition of GSK-3? using isoform-specific inhibitors could be a viable therapeutic strategy to limit PO-induced heart failure.

SUBMITTER: Ahmad F 

PROVIDER: S-EPMC6502694 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature