Abstract
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.
Footnotes
The work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL089405] and the American Heart Association National Center [Grant 0735458N] (to T.C.Z.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- HAT
- histone acetyltransferase
- HDAC
- histone deacetylase
- MI
- myocardial infarction
- TSA
- trichostatin A
- BrdU
- 5-bromo-2-deoxyuridine
- TNF-α
- tumor necrosis factor α
- ESC
- embryonic stem cell
- CSC
- cardiac stem cell
- LV
- left ventricular
- LVEDP
- LV end-diastolic pressure
- LVDP
- LV developed pressure
- LV dP/dtmax
- LV dP/dt maximum
- LV dP/dtmin
- LV dP/dt minimum
- RPP
- rate pressure product
- HR
- heart rate
- CF
- coronary effluent
- α-SMA
- α-smooth muscle actin
- vWF
- von Willebrand factor
- pH3
- phosphorylated histone 3.
- Received November 11, 2011.
- Accepted January 12, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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