The Role of Pak2 in the Heart

Abstract

Heart failure induced by cardiac hypertrophy is associated with a high mortality rate and shows continually increased prevalence and incidence. Cardiac hypertrophy is a compensatory response induced by increased physiological and mechanical stress stimulus for maintaining cardiac function. However, prolonged cardiac hypertrophy can lead to cardiac dysfunction. An in-depth understanding of the pathways involved in cardiac hypertrophy and heart failure has significant therapeutic potential for the development of effective treatment. P21-activated kinase 2 (Pak2), a member of the Ser/Thr kinase family, acts as a key regulator of cell survival and cell proliferation. The mechanisms of Pak2 involved in the regulation of cardiac function remain unclear. To elucidate the biological roles and signalling mechanisms of Pak2 in the heart, mice with cardiomyocyte-specific deletion of Pak2 (Pak2cko) and cardiomyocyte-specific overexpression of constitutively active Pak2 (Pak2Tg) were generated in this study for comparison with wild type control animals. Wild type mice were also studied in addition to Pak2cko and Pak2Tg mice. In response to pressure overload, Pak2cko mice developed exacerbated cardiac hypertrophy with impaired cardiac function, increased cardiomyocyte apoptosis and enhanced activity of caspase 7. Pak2Tg mice consistently displayed less cardiac hypertrophy with improved cardiac performance, less cardiomyocyte apoptosis and decreased activity of caspase 7 compared to the control group subject to the same pressure overload. Interestingly, blocking the MKK6/p38 pathway made Pak2cko mice resistant to the cardiac fibrosis induced by pressure overload. However, Pak2Tg mice did not exhibit increased cardiac fibrosis or increased activity of MKK6 and p38 compared to the control group in response to pressure overload. Furthermore, neonatal rat cardiomyocytes (NRCM) with deletion of Pak2 exhibited less unfolded protein response (UPR) compared to the control group after tunicamycin (TM) treatment. In conclusion, this study has demonstrated that Pak2 has a protective role against cardiac hypertrophy and may play a role in ER stress. Pak2 likely prevents cardiomyocyte apoptosis by inhibiting caspase 7 activity. Pak2 can also regulate cardiac fibrosis through the downregulation of MKK6/p38 pathway. Taken together, this thesis has advanced the knowledge about biological functions of Pak2 in the heart.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Elizabeth Cartwright (Supervisor) & Xin Wang (Supervisor)