Cardiovascular Laboratories, Department of Surgery, Boston University Medical School, Roger William Medical Center, 50 Maude Street, Providence, RI 02908, USA.
J Pharmacol Exp Ther. 2012 Apr;341(1):285-93. doi: 10.1124/jpet.111.189910. Epub 2012 Jan 23.
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.
我们之前已经证明，组蛋白去乙酰化酶（HDACs）的抑制可保护心脏免受急性心肌缺血再灌注损伤。我们还证明，HDAC 抑制可在胚胎干细胞培养模型中刺激肌生成和血管生成。我们研究了体内 HDAC 抑制是否通过刺激内源性再生来保护心脏功能并预防小鼠心肌梗死（MI）中的心脏重构。通过结扎左冠状动脉下降支来创建 MI。将动物分为三组：1）假手术组，仅进行开胸但不进行 MI；2）MI 组，进行 MI；3）MI+曲古抑菌素 A（TSA）组，MI 动物接受每日腹腔注射 TSA。此外，梗死小鼠每天接受 TSA（0.1mg/kg），一种选择性 HDAC 抑制剂的腹腔内注射。每隔一天给予 5-溴-2-脱氧尿苷（50mg/kg）以脉冲追踪标记体内内源性心脏复制。8 周后，MI 心脏显示心室收缩性降低。HDAC 抑制可改善 MI 后的心肌功能恢复，这与预防心肌重构和减少心肌和血清肿瘤坏死因子-α有关。HDAC 抑制增强了新心肌细胞和微血管的形成，这与 MI 心脏中增殖和细胞分裂的明显增加一致。在接受 TSA 治疗的 MI 心脏中观察到血管生成反应增加。值得注意的是，TSA 处理显著抑制了 HDAC 活性并增加了 Akt-1 的磷酸化，但降低了活性 caspase 3。综上所述，我们的结果表明，HDAC 抑制通过刺激心脏内源性再生来保护心脏功能并减轻心肌重构。
