| First Author | Ahmad F | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 130 |
| Pages | 65-75 | PubMed ID | 30928428 |
| Mgi Jnum | J:275923 | Mgi Id | MGI:6305006 |
| Doi | 10.1016/j.yjmcc.2019.03.020 | Citation | Ahmad F, et al. (2019) Cardiomyocyte-GSK-3alpha promotes mPTP opening and heart failure in mice with chronic pressure overload. J Mol Cell Cardiol 130:65-75 |
| abstractText | Chronic pressure-overload (PO)- induced cardiomyopathy is one of the leading causes of left ventricular (LV) remodeling and heart failure. The role of the alpha isoform of glycogen synthase kinase-3 (GSK-3alpha) in PO-induced cardiac remodeling is unclear and its downstream molecular targets are largely unknown. To investigate the potential roles of GSK-3alpha, cardiomyocyte-specific GSK-3alpha 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 2weeks of TAC. At 4week, 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 (6wk). 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-3alpha was found to regulate mitochondrial permeability transition pore (mPTP) opening and GSK-3alpha-deficient mitochondria showed delayed mPTP opening in response to Ca(2+) overload. Consistently, overexpression of GSK-3alpha 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-3alpha regulates mPTP opening under pathological conditions, likely through Bax overexpression. Genetic ablation of cardiomyocyte GSK-3alpha protects against chronic PO-induced cardiomyopathy and adverse LV remodeling, and preserves contractile function. Selective inhibition of GSK-3alpha using isoform-specific inhibitors could be a viable therapeutic strategy to limit PO-induced heart failure. |
