Mechanisms underlying the role of SMYD2 in cardiovascular disease. a Under non-stressed conditions, SMYD2 interacts with HSP90 and the N2A domain of titin to monomethylate HSP90 at lysine 616 (HSP90K616me1), and this complex can prevent the degradation of titin by MMP2 and Calpain 1. On the other hand, this complex protects the sarcomeric I-band region and myocyte organization to maintain cardiac function and sarcomere stabilization. b Upon stimulation with reactive oxidative species (ROS), SMYD2 is glutathionylated at Cys13, which leads to the dissociation of Hsp90 and titin. Then, titin is degraded by activated MMP2 to affect sarcomere destabilization. c Upon stimulation with cobalt chloride (CoCl2) or myocardial infarction (MI), the expression level of SMYD2 is decreased, which results in a reduction in p53 methylation (p53K370me1), increased p53 stability, and the induction of cardiomyocyte apoptosis.