Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart against ischemia/reperfusion injury by limiting TNFα-induced mitochondrial injury in experimental diabetes.

AIMS: The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A, reduces myocardial ischemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments activity of HDAC6 and generation of tumor necrosis factor α (TNFα) and impairs mitochondrial complex I (mCI). Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI. METHODS AND RESULTS: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNFα, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of ATP. Importantly, genetic disruption of HDAC6 or tubastatin A decreased TNFα levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or tubastatin A treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. CONCLUSIONS: HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNFα-induced mitochondrial injury in experimental diabetes.

Guías ACC/AHA 2006. Estado del arte de la evaluación cardiovascular perioperatoria para cirugía no cardiaca: Enfocado en la terapia perioperatoria con betabloqueadores / Guides ACC/AHA 2006. State-of-the-art of the cardiovascular evaluation perioperatoria for surgery noncardiac: Focused in the therapy perioperatoria with betabloqueadores

Reporte de la fuerza de Trabajo sobre Guías de Práctica del Colegio Americano de Cardiología ACC y la Asociación Americana del Corazón AHA (Comité de actualización de las Guías para la evaluación cardiovascular preoperatoria para cirugía no cardiaca). Desarrollado en colaboración con la American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Angiography and Interventions, Society for Cardiovascular Medicine and Biology. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society for Vascular Medicine and Biology. Notas: Este documento fue aprobado por la Fundación Comité del Colegio Americano de Cardiología (ACC) en Marzo de 2006 y por el Consejo Asesor y Consultor de Ciencias de la Asociación Americana de Corazón (AHA) en febrero de 2006. Cuando cite este documento el Colegio Americano de Cardiología requiere el siguiente formato de citación: Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF. ACC/AHA 2006 Guideline Update on Perioperative Cardiovascular...