ER protein misfolding is sensed in the rough ER by ATF6, which is expressed in all mammalian cells. We previously showed that in ventricular myocytes, in vivo, ischemia causes ER protein misfolding, which is sensed by ATF6, converting it to a transcription factor that induces antioxidant genes that were not known to be ATF6-regulated in any cell type. Our objective here is to study a new role for ATF6 as a critical element in regulated secretion, focusing on atrial natriuretic peptide (ANP), a peptide hormone made in the ER of atrial myocytes. Neither the function of ATF6 in the atria, nor its role in regulated hormone secretion has been studied. Therefore, this proposal addresses a novel role for ATF6 as a linchpin in regulated hormone secretion using a cardiac model system that we call the ATF6-ANP axis. Our preliminary data showed that under non- stressed conditions, in contrast to ventricular cell and tissue, activated ATF6 was found in atrial cell and tissue, even in the absence of ER stress. While activated ATF6 did not increase ANP gene expression in the atria, it was required for ANP secretion from atrial myocytes. Mechanistically, we found that ATF6 induced several secretory pathway proteins that were not previously known to be ATF6-regulated and have not been studied in the heart, including the SNARE protein, SNAP23. SNAP23 is known to enhance granule docking and secretion in other cell types. Based on this background and preliminary data, our hypothesis is that ATF6 is essential for the secretion and beneficial cardiovascular (CV) effects of ANP. SNAP23 is a mechanistic link between ATF6 and regulated ANP secretion. We will address this hypothesis in three specific aims, which are to: 1- examine the effects of AAV9- and small molecule-based ATF6 gain-of-function, and conditional ATF6 gene deletion maneuvers on ANP secretion from atrial myocytes and mouse hearts, 2-determine how ATF6 gain- and loss-of-function affects plasma ANP and hemodynamic parameters in mouse models of dietary high-salt- induced hypertension and pressure overload-induced heart failure, and 3-define the mechanistic role of the ATF6-inducible secretory granule docking protein, SNAP23, in ANP secretion from cultured atrial myocytes and mouse hearts.

Public Health Relevance

The proposed project is relevant to public health and the NIH mission, because it addresses hypertension and heart failure, which account for 1 in 7 deaths in the U.S., or nearly 400,000 deaths per year. The proposed research examines novel approaches designed to determine the role of a master regulator of protein folding in the heart, ATF6, in the secretion of the cardiac hormone, ANP, which is a potent endogenous modulator of blood pressure and heart failure. The overall goal is to provide the information necessary to design new therapies for decreasing morbidity and mortality related to hypertension and heart failure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Schwartz, Lisa
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San Diego State University
Schools of Arts and Sciences
San Diego
United States
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