Histone Deacetylase Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy

• Published in: Circulation (New York, N.Y.) Vol. 129; no. 10; pp. 1139 - 1151
• Main Authors: Xie, Min, Kong, Yongli, Tan, Wei, May, Herman, Battiprolu, Pavan K., Pedrozo, Zully, Wang, Zhao V., Morales, Cyndi, Luo, Xiang, Cho, Geoffrey, Jiang, Nan, Jessen, Michael E., Warner, John J., Lavandero, Sergio, Gillette, Thomas G., Turer, Aslan T., Hill, Joseph A.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 11.03.2014; Lippincott Williams & Wilkins
• Subjects: Animals; Animals, Genetically Modified; Apoptosis - drug effects; Autophagy - drug effects; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Coronary heart disease; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Heart; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - drug effects; Humans; Hydroxamic Acids - pharmacology; Hydroxamic Acids - therapeutic use; Male; Medical sciences; Mice; Mice, Inbred C57BL; Myocardial Infarction - pathology; Myocardial Infarction - prevention & control; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Rabbits; Rats; Rats, Sprague-Dawley; Heart; Myocardial infarction; autophagy; Injury; Cardiovascular disease; reperfusion injury; Coronary heart disease; Myocardial disease; Trauma; Myocyte; Reperfusion; Ischemia; Cell death; Blunted effect; histone deacetylases; Circulatory system; Inhibition; Lesion; Cardiology; Histone; cell death; myocardial infarction
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.002416

BACKGROUND—Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. METHODS AND RESULTS—Twenty-one rabbits were randomly assigned to 3 groups(1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA’s cardioprotective effects. CONCLUSIONS—The US Food and Drug Administration–approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.