PT  - JOURNAL ARTICLE
AU  - Ling Zhang
AU  - Xin Qin
AU  - Yu Zhao
AU  - Loren Fast
AU  - Shougang Zhuang
AU  - Paul Liu
AU  - Guangmao Cheng
AU  - Ting C. Zhao
TI  - Inhibition of Histone Deacetylases Preserves Myocardial Performance and Prevents Cardiac Remodeling through Stimulation of Endogenous Angiomyogenesis
AID  - 10.1124/jpet.111.189910
DP  - 2012 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 285--293
VI  - 341
IP  - 1
4099  - http://jpet.aspetjournals.org/content/341/1/285.short
4100  - http://jpet.aspetjournals.org/content/341/1/285.full
SO  - J Pharmacol Exp Ther2012 Apr 01; 341
AB  - We have previously shown that the inhibition of histone deacetylases (HDACs) protects the heart against acute myocardial ischemia and reperfusion injury. We also demonstrated that HDAC inhibition stimulates myogenesis and angiogenesis in a cultured embryonic stem cell model. We investigate whether in vivo inhibition of HDAC preserves cardiac performance and prevents cardiac remodeling in mouse myocardial infarction (MI) through the stimulation of endogenous regeneration. MI was created by ligation of the left descending artery. Animals were divided into three groups: 1) sham group, animals that underwent thoracotomy without MI; 2) MI, animals that underwent MI; and 3) MI + trichostatin A (TSA), MI animals that received a daily intraperitoneal injection of TSA. In addition, infarcted mice received a daily intraperitoneal injection of TSA (0.1 mg/kg), a selective HDAC inhibitor. 5-Bromo-2-deoxyuridine (50 mg/kg) was delivered every other day to pulse-chase label in vivo endogenous cardiac replication. Eight weeks later, the MI hearts showed a reduction in ventricular contractility. HDAC inhibition increased the improvement of myocardial functional recovery after MI, which was associated with the prevention of myocardial remodeling and reduction of myocardial and serum tumor necrosis factor α. HDAC inhibition enhanced the formation of new myocytes and microvessels, which was consistent with the robust increase in proliferation and cytokinesis in the MI hearts. An increase in angiogenic response was demonstrated in MI hearts receiving TSA treatment. It is noteworthy that TSA treatment significantly inhibited HDAC activity and increased phosphorylation of Akt-1, but decreased active caspase 3. Taken together, our results indicate that HDAC inhibition preserves cardiac performance and mitigates myocardial remodeling through stimulating cardiac endogenous regeneration.