Description
Following myocardial infarction or myocardial ischemia/reperfusion, damage to the heart often leads to loss of contractility, cardiac myocyte apoptosis and necrosis, and a progression towards heart failure. This is a result of events that are mediated by the impairment of calcium handling and perturbations to cellular protein quality control systems. Although clinical interventions exist to slow the progression towards heart failure, a method for repairing myocardial damage is yet to be discovered. We have shown that as a result of myocardial ischemia, toxic, misfolded proteins accumulate in the sarcolplasmic reticulum (SR) /endoplasmic reticulum (ER) leading to a condition known as ER stress. Studies done previously in our lab showed that activating transcription factor 6 (ATF6), a critical sensor and regulator of ER stress, was activated in the ischemic heart and in neonatal rat ventricular myocytes (NRVM) subjected to simulated ischemia. Moreover, ATF6 protects the heart and cardiac myocytes from ischemia or chemical inducers of ER stress. Additionally, ATF6 has been studied extensively in models of cerebral ischemia, Alzheimer's disease and diabetes. However, the role of endogenous ATF6 in the heart was not known when this thesis research began. Therefore, in order to determine a role of endogenous ATF6 in the heart, ATF6 knockout (KO) mice were subjected to surgically-induced myocardial infarction and myocardial ischemia/reperfusion. Additionally, we characterized ER stress in adult mouse ventricular myocytes (AMVM) from ATF6 KO mouse hearts in order to determine whether loss of ATF6 impaired the adaptive ER stress response in myocytes and, in so doing, increased their death in response to simulated ischemia. Compared to WT mice, the hearts of ATF6 KO mice exhibited more damage and a greater decline in heart function, as shown by an approximate decrease of 15% in the ejection fraction. In support of this, a significant decrease in cell viability was also observed in ATF6 KO AMVM when compared to AMVM from WT mice following simulated ischemia/reperfusion. Together, the results of this thesis research demonstrate that endogenous ATF6 serves a protective role in the ischemic heart and in isolated cardiac myocytes.
