Protective signaling in the myocardium [electronic resource] : a role for protein kinase cepsilon and aldehyde dehydrogenase 2 regulators in the treatment of myocardial infarction and heart failure

The nearly 9 million incidences of myocardial infarction (MI) and the resultant heart failure in the United States alone call for a continued need for the development of novel therapeutics. However, the molecular basis of these diseases is highly complex and awaits further elucidation. Our lab has a long-standing interest in determining the role of protein kinase C (PKC) in cardiovascular diseases. Elevated expression of alpha, beta, epsilon and deltaPKCs is associated with cardiac dysfunction in failing murine and human hearts. Moreover, genetic and pharmacological modulations of PKC activities exert profound impact on the state of these diseases. However, characterization of the specific role of each PKC isozyme was hampered by the lack of isozyme-selective PKC regulators. To this end, Mochly-Rosen and co-workers have rationally designed and developed isozyme-selective peptide activators and inhibitors of PKC that have enabled us to examine the role of each PKC isozyme in any biological system. Using an epsilonPKC-selective inhibitor, we found that sustained inhibition of epsilonPKC suppressed excessive cardiac fibrosis and preserved cardiac function in a rat model of hypertension-induced heart failure, in vivo. To uncover the mechanistic link between epsilonPKC and cardiac fibrosis, I showed that activation of epsilonPKC increased the activity matrix metalloproteinase-2 (MMP-2), a critical protease that degrades the extracellular matrix to facilitate cardiac fibrosis. Further, using the epsilonPKC inhibitor and cardiac fibroblasts that lack epsilonPKC, I discovered that histone deacetylase 6 (HDAC6), a cytosolic enzyme that deaceylates alpha-tubulin, participates in epsilonPKC modulation of MMP-2 activity during cardiac fibrosis. These results suggest that the epsilonPKC-selective inhibitor can be a potential therapeutic for the treatment of heart failure. Aldehyde dehydrogenase 2 (ALDH2) was identified by our group as a mitochondrial substrate for epsilonPKC that confers cardioprotection from ischemic injury. ALDH2 activation during MI is cardioprotective, because it oxidizes and thus removes toxic aldehydes that accumulate due to lipid peroxidation during ischemia-reperfusion. Since these aldehydes form protein adducts that inactive many cellular enzymes, they contribute to non-reversible damage to the ischemic myocardium. A recent study discovered that ALDH2 is required for nitroglycerin bioactivation, in vivo, but its enzymatic activity is inhibited by prolonged treatment with nitroglycerin. This has prompted us to determine potential risks associated with nitroglycerin tolerance in association with the role that ALDH2 has in cardiac protection. The clinical implications here are of special interest to us, because any risks pertinent to nitroglycerin treatment, if validated, can affect millions of patients with cardiac diseases. Therefore, I set off to determine whether sustained nitroglycerin treatment increases injury to the ischemic myocardium using a rat model of myocardial infarction (MI). I confirmed that sustained nitroglycerin treatment, as might be given to patients with angina pectoris, inhibited ALDH2 activity in the rat myocardium, in vivo. Further, I found that continuous treatment of nitroglycerin resulted in more than 2-fold increase in infarct size and worsened cardiac function after MI, in vivo. I then used Alda-1, a selective ALDH2 activator our group discovered, to assess whether activation of ALDH2 could undo the nitroglycerin-induced cardiac injury. Indeed, concomitant treatment with Alda-1 and nitroglycerin inhibited nitroglycerin-induced increase in infarct size and restored post-MI cardiac function. This finding poses a challenge to the prevalent clinical practice: patients, under sustained nitroglycerin therapy for the management of angina pectoris, are at risk of increased cardiac damage if they develop an MI during the nitroglycerin treatment. My animal studies suggest that if Alda-1 is given together with nitroglycerin, it can reduce cardiac damage caused by nitroglycerin tolerance. Finally, to determine the mechanism underlying the role of nitroglycerin and Alda-1 in MI injury, I demonstrated that Alda-1 prevented nitroglycerin-induced inactivation of ALDH2 and the resultant elevation of protein carbonylation, a hallmark of toxic aldehydic adducts, in the myocardium. The result substantiates a health mechanism for the heart: loss of control over oxidative stress leads to an injured myocardium and a simple correction of that function undoes the bad.

Keywords: Molecular Pharmacology.
Advisor: Mochly-Rosen Daria primary advisor. Thesis advisor
Bernstein Daniel
Bogyo Matthew
Wysocka Joanna