TNFα shedding in mechanically stressed cardiomyocytes is mediated by Src activation of TACE

Synthesized by the heart under hemodynamic overloading (mechanical stress), TNFα exerts complex effects on the heart -beneficial as a membrane protein and detrimental as a secreted protein, which presents a dilemma in the treatment of congestive heart failure. We postulate that by selectively blocking mechanical stress-induced cardiomyocyte secretion of TNFα, a function of TNFα converting enzyme (TACE), the detrimental effect of TNFα can be mitigated. However, the mechanism through which mechanical stress activates TACE in cardiomyocytes is unknown. Here, we report a molecular mechanism that mediates TACE activation in mechanically stressed cardiomyocytes. We found that the non-receptor tyrosine kinase Src mediates TACE activation in mechanically stretched rat cardiomyocytes by phosphorylating the Tyr-702 residue within the intracellular tail of TACE. The rapid activation of Src in mechanically stretched cardiomyocytes is followed by TACE phosphorylation on Tyr-702, leading to activation of p38 MAPK, a kinase that is an effector of TNFα receptor activation. Pharmacological inhibition or silencing of Src attenuated stretch-induced TACE phosphorylation on Tyr-702 and p38 activation. Overexpression of a TACE mutant in which Tyr-702 was replaced by alanine (TACE-Y702A) attenuated stretch-induced TNFα release from cardiomyocytes as well as activation of p38. These data suggests that Src mediates TACE activation in mechanically stressed cardiomyocytes and this mechanism could be exploited for specific blockade of TNFα secretion and its detrimental effects in congestive heart failure.