Investigation into the role of Pak2 in the heart following myocardial infarction

Abstract

Myocardial infarction (MI) and cardiac hypertrophy are two principal causes of heart failure, which affects millions of people worldwide and for which prognosis remains poor. Previous research has identified p21-activated kinase 2 (Pak2) as a cardioprotective molecule during cardiac hypertrophy by regulating the ER stress response. This project aimed to determine whether Pak2 has a protective role in the heart following MI. Pak2 cardiomyocyte-specific knockout mice (Pak2cko) were used to investigate Pak2's role in vivo, and MI was induced through permanent ligation of the left anterior descending coronary artery. Western blot analysis demonstrated that Pak2 is activated in the acute MI response. Cardiac function was not affected by Pak2 knockout after two weeks. However, Pak2cko mice exhibited increased cell death and cardiac fibrosis two days following MI. Molecular analysis found an increase in protein levels of C/EBP homologous protein (Chop), demonstrating an impaired ER stress response in these mice. To investigate the role of Pak2 in vitro, H9c2 cardiomyoblasts were exposed to MI-mimicking stressors. Pak2 was found to be activated after 2 hours of hypoxia (100 % N2) combined with nutrient starvation, and 1 hour after induction of oxidative stress by hydrogen peroxide (100 microM). Under these conditions, adenovirus-mediated Pak2 knockdown demonstrated that Pak2 deficiency leads to an impaired ER stress response. These findings suggest that Pak2 is a cardioprotective factor in response to MI-related stresses through modulation of the cardiomyocyte ER stress response.

Date of Award	28 Jan 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Elizabeth Cartwright (Co Supervisor), Xin Wang (Main Supervisor) & Wei Liu (Co Supervisor)