Elucidating The Role Of Peptidyl tRNA Hydrolase 2 In The Heart
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2023
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University of Hawaii at Manoa
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Abstract
Peripartum cardiomyopathy (PPCM) is a form of maternal heart failure that presents with left ventricular dysfunction and may lead to heart failure and death. PPCM occurs during the last month of pregnancy or within five months after delivery in previously healthy women. PPCM is a condition of unknown etiology. Previous hypotheses have pointed at hemodynamical stresses as the underlying cause of PPCM. More recently, a genetic predisposition approach has gained more interest in explaining the pathophysiology of PPCM. Peptidyl tRNA hydrolase 2 (PTRH2) has been identified as a key regulator in skeletal muscle development and myogenic differentiation. PTRH2 has also been shown to transmit mechanosensory signals by interaction with an integrin-FAK complex to induce survival in attached cells. Additionally, biallelic mutations in Ptrh2 gene cause an infantile multisystem neurologic-endocrine-pancreatic disease (IMNEPD) in humans. We found that left ventricular expression of PTRH2 increases upon pregnancy in non-transgenic (Ptrh2-flox/flox, Ptrh2-NT) mice. We developed a heart specific knockout of PTRH2 (Ptrh2-CKO) and found that all pregnant female mice develop a pregnancy-induced phenotype like that of PPCM patients. Here, we report a novel hypothesis of mechano-transduction for the pathogenesis of PPCM in which PTRH2 is the key player. We hypothesize that PTRH2 may be protecting the heart by acting as a cardiac mechano-sensor in response to pregnancy-induced pressure overload. Additionally, we performed histological, echocardiographic, gene and protein expression analyses to characterize the PPCM phenotype in the female Ptrh2-CKO mice hearts compared to pregnant Ptrh2-NT controls as well as proteomics analyses and yeast-two hybrid screening to identify interacting partners of PTRH2. Co-immunofluorescence staining, proximity ligation, co-immunoprecipitation and pull-down assays were carried out to confirm direct interactions. Human samples from PPCM and dilated cardiomyopathy (DCM) patients were also analyzed by whole exome sequencing (WES) for potential Ptrh2 gene mutations. Our results showed that Ptrh2-CKO mice exhibit left ventricular enlargement and hypertrophy that transitions into dilated cardiomyopathy Post-Partum. These cardiac mechanical stresses ultimately lead to heart failure as confirmed by histology, echoes, and gene expression analyses. Yeast-two hybrid screening and proteomic analyses identified cardiac beta-myosin heavy chain (β-MHC) and myosin regulatory light chain (MYL2), cardiac regulators of contractility, as potential interacting partners for PTRH2. Further, β-MHC and PTRH2 were found to form a complex in solution and co-localize at the Z-disc, a dynamic sarcomere structure that regulates signal transduction across the myofibrils during contraction. Loss of Ptrh2 also disrupted sarcomere arrangement and Ptrh2-CKO mice exhibited decreased contractility function leading to heart failure. Human WES revealed a potential homozygous deletion of Ptrh2 that may be contributing to the PPCM phenotype in patients. Altogether, these findings suggest PTRH2 as a potential modulator of pregnancy-induced cardiac stress and as an essential mechano-transducer in the heart via cardiac β-MHC.
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Heart diseases in pregnancy, Peripartum cardiomyopathy, Heart--Diseases--Etiology, Heart--Pathophysiology
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