Abstract 19423: ATF6 Serves a Novel Role as an Integrator of the Antioxidation and Adaptive ER Stress Responses in the Heart
Introduction: Secreted and membrane proteins are synthesized and folded in the endoplasmic reticulum (ER). We previously showed that myocardial ischemia increases ER protein misfolding and activates the ER stress response, which is initially adaptive, fostering myocyte survival. However, if left unresolved, the ER stress response is maladaptive leading to myocyte death. ATF6 is an ER-transmembrane protein that senses misfolded proteins in the ER, and then becomes a transcription factor that induces ER stress response genes encoding ER proteins that adaptively restore ER protein folding. We previously showed that compared to non-transgenic mice, the hearts of ATF6 transgenic mice had better function and less damage upon ischemia/reperfusion (I/R); however, the mechanism of these protective effects is not known.
Methods: Here, PCR gene array results showed that in cardiac myocytes, ATF6 induces genes encoding antioxidant proteins residing outside the ER, one of which is catalase. Thus, we explored the functions of ATF6-mediated catalase induction in the oxidative stress response during I/R in cardiac myocytes, in vitro and in vivo.
Results: In vitro, overexpression of ATF6 in neonatal rat ventricular myocytes (NRVMs) induced protective ER stress response genes, while reducing reactive oxygen species (ROS), and necrotic cell death in cells treated with H2O2 or simulated I/R (sI/R); ATF6 knockdown had the opposite effects. Catalase knockdown in NRVMs increased ROS, and necrotic cell death in cells treated with sI/R. ATF6 bound to putative ER stress response elements in the catalase gene and activated the catalase promoter. Mutation of these elements ablated ATF6 binding and ATF6-mediated catalase promoter activation. In vivo, compared to wild type, ATF6 knockout mouse hearts exhibited decreased catalase expression, reduced function and greater damage in response to myocardial infarction or I/R.
Conclusions: This is the first demonstration in any cell type that ATF6 is critical for the adaptive oxidative stress response and the adaptive ER stress response, and describes a novel mechanism of ATF6-mediated protection of the heart from ischemic damage.
Author Disclosures: J. Jin: None. K. Azizi: None. D.J. Thuerauf: None. E.A. Blackwood: None. A.G. Fahem: None. S. Doroudgar: None. C.C. Glembotski: None.
- © 2016 by American Heart Association, Inc.