Abstract 11017: Hdac Inhibition Elicits in vivo Endogenous Myocardial Regeneration Through C-Kit+ Cardiac Stem Cells in Infarcted Hearts
Background: The adult mammalian myocardium harbors resident cardiac stem cells (CSCs) that have the potential to generate new myocardium. However, the in vivo potential of endogenous CSCs to facilitate myocardial regeneration has not been fully understood.
Objective: Our goal was to investigate whether HDAC inhibition elicits a direct endogenous myocardial regeneration through the c-kit+ CSCs and, whether regeneration results in restoration of cardiac function and prevention of remodeling.
Methods: Wild type Kit+/+ and KitW/KitW-v mice were used, and myocardial infarction (MI) was induced by ligation of the left descending coronary artery. Infarcted mice received a daily intraperitoneal injection of trichostatin A (TSA, 0.1mg/kg), a selective HDAC inhibitor. 5-bromo-2-deoxyuridine (BrdU, 50 mg/kg) was delivered to pulse-chase label in vivo endogenous cardiac regeneration. Eight weeks after MI, cardiac function was measured in Langendorff mode. BrdU, Ki67, phosphorylated-histone 3, c-kit+CSC, newly formed myocytes, and microvessels were determined. Cardiac morphology was examined by Masson trichrome stainings.
Results: Administration of TSA to infarcted Kit+/+ mice significantly increased the recovery of left ventricular (LV) systolic pressure, left ventricular developed pressure, and LV dP/dt as compared to the MI control group (p<0.05), which were eliminated in KitW/KitW-v mice. Infarcted Kit+/+ mice treated with TSA had smaller infarctions and a more viable myocardium relative to infarcted KitW/KitW-v hearts. The numbers of c-kit+ CSCs and BrdU positive newly formed myocytes and microvessles were markedly increased in MI+Kit+/+ mice compared to MI+KitW/KitW-vmice. Ki67, phosphorylated-histone 3 positive nuclei, and myocytes were elevated in MI+Kit+/+ vs MI+KitW/KitW-v heart.
Conclusion: HDAC inhibition induces in vivo endogenous myocardial regeneration, which depends on the activation of c-kit+ CSCs following MI.
- © 2011 by American Heart Association, Inc.