Involvement of Endoplasmic Reticulum Stress-Mediated Activation of C/EBP Homologous Protein in Aortic Regurgitation-Induced Cardiac Remodeling in Mice.

Abstract	Aortic regurgitation (AR) is a volume overload disease causing eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Endoplasmic reticulum (ER) stress and ER stress-mediated apoptosis is involved in many cardiovascular diseases, but whether they also participate in AR-induced heart failure is still elusive. In this study, we found ER stress activation in myocardial samples from patients with AR. With a unique murine model of AR which induced eccentric cardiac hypertrophy and heart failure, we also found aggravation of cardiac ER stress and apoptosis, as evidenced by a reduction of Bcl-2/Bax ratio and an increase of caspase-3 cleavage. We then examined the signaling effectors involved in ER-initiated apoptosis and found volume overload specifically activated C/EBP homologous protein (CHOP), but not caspase-12 or Jun N-terminal kinase (JNK). Interestingly, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, improved cardiac function, and suppressed ER stress, apoptosis, and CHOP. Furthermore, genetic knockdown of CHOP inhibited cardiac Bcl-2/Bax ratio reduction and caspase-3 activation and rescued cardiac dysfunction. In summary, our findings suggest that ER stress-CHOP signaling is involved in the development of volume overload cardiac hypertrophy induced by AR through promoting cardiomyocytes apoptosis and provide a previously unrecognized target in heart failure induced by volume overload.
Authors	Xingxu Wang, Wei Wei, Jian Wu, Le Kang, Shuangquan Wu, Jiming Li, Yunli Shen, Jieyun You, Yong Ye, Qi Zhang, Yunzeng Zou
Journal	Journal of cardiovascular translational research (J Cardiovasc Transl Res) Vol. 15 Issue 2 Pg. 340-349 (04 2022) ISSN: 1937-5395 [Electronic] United States
PMID	34426929 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Topics	Animals Aortic Valve Insufficiency Apoptosis Endoplasmic Reticulum Stress Heart Humans Mice Mice, Inbred C57BL Myocytes, Cardiac (metabolism) Ventricular Remodeling

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