Pak2 Regulation of Nrf2 Serves as a Novel Signaling Nexus Linking ER Stress Response and Oxidative Stress in the Heart

Frontiers in Cardiovascular Medicine

Jonathan Chernoff¹  Norbert Frey²  Min Zi⁴  Elizabeth J. Cartwright⁴  Xin Wang⁴  Lucy Collins⁴  Pablo Binder⁴  Foteini Christou⁴  Wei Liu⁴  Binh Nguyen⁴  Oliver J. Müller⁵  Susanne S. Hille⁵  Xiaojing Luo⁶  Kaomei Guan⁶ 

[1] Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, United States;Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany;Department of Internal Medicine III, University of Kiel, Kiel, Germany;Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom;German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, Hamburg, Germany;Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany;

关键词: heart failure;    oxidative stress;    ER stress;    RAAS and oxidative stress;    proteostasis;    gene therapy;   

DOI  :  10.3389/fcvm.2022.851419

来源: DOAJ

【 摘 要 】

Endoplasmic Reticulum (ER) stress and oxidative stress have been highly implicated in the pathogenesis of cardiac hypertrophy and heart failure (HF). However, the mechanisms involved in the interplay between these processes in the heart are not fully understood. The present study sought to determine a causative link between Pak2-dependent UPR activation and oxidative stress via Nrf2 regulation under pathological ER stress. We report that sustained ER stress and Pak2 deletion in cardiomyocytes enhance Nrf2 expression. Conversely, AAV9 mediated Pak2 delivery in the heart leads to a significant decrease in Nrf2 levels. Pak2 overexpression enhances the XBP1-Hrd1 UPR axis and ameliorates tunicamycin induced cardiac apoptosis and dysfunction in mice. We found that Pak2 deletion and altered proteostasis render Nrf2 detrimental by switching from its antioxidant role to renin-angiotensin aldosterone system (RAAS) gene regulator. Mechanistically, Pak2 mediated Hrd1 expression targets Nrf2 for ubiquitination and degradation thus preventing its aberrant activation. Moreover, we find a significant increase in Nrf2 with a decrease in Pak2 in human myocardium of dilated heart disease. Using human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we find that Pak2 is able to ameliorate Nrf2 induced RAAS activation under ER stress. These findings demonstrate that Pak2 is a novel Nrf2 regulator in the stressed heart. Activation of XBP1-Hrd1 is attributed to prevent ER stress-induced Nrf2 RAAS component upregulation. This mechanism explains the functional dichotomy of Nrf2 in the stressed heart. Thus, Pak2 regulation of Nrf2 homeostasis may present as a potential therapeutic route to alleviate detrimental ER stress and heart failure.

【 授权许可】

Unknown