Peptidyl-tRNA hydrolase 2 is an essential negative regulator of peripartum cardiomyopathy with maternal heart failure (human and mouse RNA-seq)

The peptidyl-tRNA hydrolase 2 (PTRH2, Bit-1; BIT1) gene plays a pro-survival role during development with loss of function gene mutations causing congenital infantile multisystem disease (IMNEPD). In wild-type female mice hearts, ptrh2 protein levels significantly increase during pregnancy and decrease postpartum, demonstrating a protective role in response to pregnancy-initiated cardiac stresses. Peripartum cardiomyopathy (PPCM) is due to dysregulated protective signaling in the pregnant heart. The genetic and molecular mechanisms underlying PPCM remain poorly defined with no specific therapies. Here, we engineered a cardiac-specific Ptrh2 knockout (Ptrh2-CKO) mouse and show these maternal mice develop left ventricular systolic dysfunction, exhibit high rates of postpartum heart failure, and model key features of human PPCM. Infusion of a caspase 3-specific inhibitor attenuated the PPCM phenotype. Collectively, our findings demonstrate Ptrh2 is a negative regulator of pregnancy-induced cardiac stresses by activating pro-survival signals and blocking apoptotic signals, suggesting Ptrh2 may be a therapeutic target for the treatment of PPCM