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

Frontiers in Cardiovascular Medicine

article

Jonathan Chernoff¹  Oliver J. Müller²  Kaomei Guan⁴  Xin Wang⁵  Pablo Binder⁵  Binh Nguyen⁵  Lucy Collins⁵  Min Zi⁵  Wei Liu⁵  Foteini Christou⁵  Xiaojing Luo⁴  Susanne S. Hille²  Norbert Frey⁶  Elizabeth J. Cartwright⁵ 

[1] Cancer Biology Program, Fox Chase Cancer Center;Department of Internal Medicine III, University of Kiel;German Center for Cardiovascular Research;Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universitaet Dresden;Faculty of Biology, Medicine and Health, The University of Manchester;Department of Cardiology, Angiology and Pneumology, University of Heidelberg

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

DOI  :  10.3389/fcvm.2022.851419

学科分类：地球科学(综合)

来源: Frontiers

【 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】

CC BY