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

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.
Source: Journal of Cardiovascular Translational Research - Category: Cardiology Source Type: research