Myocardial ischemia causes ER stress and potentially lethal ER protein misfolding. The adaptive ER stress response restores ER protein folding and fosters myocyte survival. If this process is not sufficient to restore ER protein folding, the ensuing maladaptive ER stress response leads to myocyte death. To survive the hypoxic environment in tumors, cancer cells have evolved an exaggerated adaptive ER stress response, mediated partly by the transcription factor, ATF6, which is activated by ER stress. Compared to cancer cells, normal cells have relatively little ATF6 and a weak adaptive ER stress response. Our preliminary data showed that ATF6 deletion increased infarct size and decreased function in mouse hearts subjected to myocardial infarction. The objective of the proposed research is to examine the molecular mechanism of ATF6 function in the heart, which will reveal new information needed to develop novel therapies for ischemic heart disease based on harnessing the adaptive ER stress response in the heart. In our previous studies, we were surprised to find that activated ATF6 is rapidly degraded; this degraded-when-active property suggests that strict regulation of the level of ATF6 and the genes it regulates, must have functional significance; however, this significance has not been examined. Our hypotheses are as follows: 1- Endogenous ATF6 adaptively decreases apoptosis and infarct size upon ischemia, which improves post-ischemia myocardial recovery. 2- ATF6 is degraded when active because short-term ATF6 activation is adaptive, while long-term ATF6 activation is maladaptive. 3- Activation of endogenous ATF6 with small molecule activators is adaptive, and because it is reversible, we can regulate dose and time to maximize adaptive and minimize maladaptive effects of ATF6 activation to optimize therapeutic potential. These three hypotheses will be addressed by the following corresponding Specific Aims: 1- To assess the effects of endogenous ATF6 deletion on cardiac structure and function in an MI model of heart failure using ATF6 knockout (KO) mice. 2- To use AAV9-mediated gene transfer of forms of ATF6 that exhibit a range of degraded-when-active properties into ATF6 KO mice, then assess the effects of these forms of ATF6 on cardiac structure and function in an MI model of heart failure. 3- To determine the effects of novel small molecule activators of endogenous ATF6 on the viability and on ER stress signaling, initially in isolated cardiac myocytes and then and in mice, in vivo.
The proposed project is relevant to public health and the NIH mission, because it addresses ischemic heart diseases, including myocardial infarction, which accounts for 1 in 6 deaths in the U.S., or nearly 400,000 deaths per year. The proposed research examines novel approaches designed to co-opt mechanisms by which tumor cells thwart death from ischemia, and adapt these mechanisms to the heart. The overall goal is to provide the information necessary to design novel, more effective therapies for protecting the heart from ischemic damage from myocardial infarction, which would reduce the morbidity and mortality related to this disease.
