Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.

Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate-limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte-specific knockout mice were generated by crossing the floxed mice with α-MHC (myosin heavy chain)-Cre transgenic mice, and cardiac specific overexpression mice were established by injecting adeno-associated virus serotype 9 system. The results showed that cardiomyocyte-specific deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas overexpression mitigated transverse aortic constriction-induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)-MAPK (mitogen-activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload-induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.