S-nitrosylation of transglutaminase 2 impairs fatty acid-stimulated contraction in hypertensive cardiomyocytes.

The myocardium in hypertensive heart exhibits decreased fatty acid utilization and contractile dysfunction, leading to cardiac failure. However, the causal relationship between metabolic remodeling and cardiomyocyte contractility remains unestablished. Transglutaminase 2 (TG2) has been known to promote ATP production through the regulation of mitochondrial function. In this study, we investigated the involvement of TG2 in cardiomyocyte contraction under fatty acid supplementation. Using TG2 inhibitor and TG2-deficient mice, we demonstrated that fatty acid supplementation activated TG2 and increased ATP level and contractility of cardiac myocyte from the normal heart. By contrast, in cardiac myocytes from angiotensin-II-treated rats and mice, the effects of fatty acid supplementation on TG2 activity, ATP level, and myocyte contraction were abolished. We found that TG2 was inhibited by S-nitrosylation and its level increased in hypertensive myocytes. Treatment with inhibitor for neuronal NOS restored fatty acid-induced increase of TG2 activity and myocyte contraction. Moreover, intracellular Ca2+ levels were increased by fatty acid supplementation in both normal and hypertensive myocytes, showing that S-nitrosylation of TG2 but not alteration of intracellular Ca2+ levels is responsible for contractile dysfunction. These results indicate that TG2 plays a critical role in the regulation of myocyte contractility by promoting fatty acid metabolism and provide a novel target for preventing contractile dysfunction in heart with high workload.