Regulatory mechanisms of AMP-activated protein kinase in limiting myocardial infarction
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Ischemic heart disease and myocardial infarction contribute to the leading cause of morbidity and mortality in the United States. Emergent restoration of coronary patency via anticoagulants, thrombolytics, and percutaneous coronary intervention (PCI), is currently the gold standard for patients presenting with acute coronary syndromes. However, prolonged ischemia followed by immediate reperfusion has been shown to escalate the process of cell death and increase the extent of myocardial infarction. This process known as ischemia/reperfusion (I/R) injury although undesirable appears to be inevitable due to the fact that no treatments currently exist that target mechanisms within the heart to prevent cell death. Thus, there is an increasing need for novel therapeutic strategies limiting the extent of myocardial infarction as a result of I/R. Over the last several years, AMP-activated protein kinase (AMPK) has emerged as an attractive target for I/R injury in that it has been shown by several investigators to limit the extent of infarction and improve cardiac function. However, our current ability to effectively target AMPK in the setting of myocardial infarction is still in its infancy, as the mechanisms governing its regulation in the heart are incompletely understood. The studies performed in Chapter 3 further demonstrates the beneficial outcome of using rosiglitazone (RGZ), a known AMPK activator as an adjuvant therapy to reperfusion after a prolonged ischemic insult in the mouse. When giving RGZ acutely to a non-diabetic mouse in the setting of myocardial I/R, myocardial infarction is decreased, and post-ischemic cardiac function is significantly improved. The mechanism of RGZ-induced cardioprotection was found to be largely due to stimulating AMPK phosphorylation. These results were confirmed when pre-treatment with Compound C, and AMPK inhibitor, blocked the cardioprotective effects of RGZ. Acute RGZ treatment was also found to affect other cardioprotective mechanisms such as enhancing the up-regulation of Akt and down-regulation of JNK phosphorylation. The experiments conducted in Chapter 4 were designed to improve our understanding of the complex mechanisms that govern AMPK activation by its upstream kinase LKB1 in the ischemic heart. Specifically, we investigated the protein Sestrin2, which has been shown to activate AMPK in response to stress, although its mechanism of how it stimulates AMPK activity has remained unknown. In this series of studies, we establish that Sestrin2 is expressed in adult mammalian cardiomyocytes and is responsive to ischemic conditions in cardiac tissue. We also demonstrate that Sestrin2 is an essential part of the adaptive response to I/R as Sestrin2 KO hearts display exacerbated myocardial infarction and impaired post-ischemic contractile function. Furthermore, we have identified a unique mechanism by which Sestrin2 promotes AMPK activation during myocardial ischemia, acting as an ischemia-induced scaffold protein that initiates AMPK phosphorylation via a time-dependent interaction with LKB1. Chapter 5 contains an overall discussion of the work conducted in this thesis and insight toward how the findings could be potentially translated to clinically relevant models of myocardial I/R. This chapter also includes preliminary insight and a discussion regarding the involvement of AMPK and Sestrin2 in myocardial hypertrophy and heart failure.