Abstract 15172: P21 Activated Kinase 2 Mediates Cardioprotection in Heart Failure With Preserved Ejection Fraction by Modulating Endoplasmic Reticulum Stress Response

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterised by diastolic dysfunction but normal systolic function. Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of HFpEF. Previous studies have reported that P21 activated kinase 2 (Pak2) confers cardioprotection against the endoplasmic reticulum stress response. Hypothesis: Pak2 protein can potentially alleviate the adverse effects of maladaptive ER stress in HFpEF. Methods: The HFpEF model was developed by feeding C57/BL6N male mice with a high-fat diet (HFD) and a constitutive nitric oxide inhibitor, L-NAME, in drinking water for 15 weeks. Cardiac function was assessed by echocardiography and hemodynamics. Heart and lung structure was detected by H&E staining and Masson staining. Electron microscopy, immunoblotting, and RNA sequencing were used to investigate the ER structure and function. Cardiomyocyte-specific Pak2 knockout (Pak2 CKO ) mice and adeno-associated virus (AAV) 9 for Pak2 overexpression were used to investigate the role of Pak2 in the heart. Results: After 15 weeks of feeding, mice on the HFD+L-NAME diet developed an HFpEF phenotype, as indicated by cardiac hypertrophy, impaired diastolic function but preserved systolic function, and pulmonary remodelling. The ER structure and the IRE1/XBP1s pathway were impaired in the cardiomyocytes of HFD+L-NAME mice. Pak2CKO mice exhibited the HFpEF phenotype at 10 weeks. In addition, Pak2 overexpression prevented diastolic dysfunction after 15 weeks and preserved the activation of the IRE1/XBP1s pathway under stress conditions. Conclusions: HFD + L-NAME diet for 15 weeks recapitulated the features of HFpEF in mice. Pak2 plays a protective role in HFpEF progression by modulating the cardiomyocyte ER stress response through the IRE1/XBP1s signaling pathway.