转录因子Hand1在小鼠心肌梗死中的作用

Myocardial infarction (MI) has a high incidence in clinical patients.Disection of its pathogenesis has a high impact on its prevention and treatment.Hand1 is a member of the basic helix-loop-helix transcription factor family.It has been founded that Hand1 expression is downregulated in ischemic cardiomyopathy compared with normal heart tissue.The preliminary data support this proposal is that we recently found that mRNA expression of Hand1 was also downregulated in mice one week after ligation of left ventricular coronary artery. These results suggest that Hand1 may be involved in myocardial infarction. However the functional role of Hand1 in the development of myocardial infarction is still unknown. In order to clarify this question, we did left ventricular cornary artery ligation on Hand1 heterozygous knock out mice and wild-type littermates to make myocardial infarction model, and found that Hand1 heterozygous knockout mice survived longer than the control mice.This result suggests that haploinsufficiency of Hand1 can protect mice under myocardial infarction.In this proposed project, we will make more myocardial infarction mouse model and elucidate the role of Hand1 and its involved pathological molecular mechanisms in myocardial infarction uing histopathologic, biochemical and molecular biological techniques.The outcome of this project will open a novel avenue to guide the clinical prevention and treatment of MI.

心肌梗死在临床上是多发疾病，研究其发病机理对其预防和治疗有重要意义。Hand1是碱性螺旋-环-螺旋转录因子家族的一员，近来研究发现,Hand1基因在缺血性心肌病人（心肌梗塞病）心脏中表达降低。我们最近研究显示，野生型小鼠给予左室冠状动脉结扎后一周内Hand1在RNA水平明显降低。这些结果提示Hand1基因可能参与了心肌梗塞的发展过程。但是Hand1下调对心肌梗死发展过程的病理生理学意义仍不清楚。为弄清这一问题，我们对Hand1基因杂合敲除小鼠与同窝对照小鼠行左室冠状动脉结扎制成心肌梗死模型，发现Hand1单倍缺失的小鼠在MI手术后存活时间更长，表明Hand1缺失对心梗有保护作用。接下来本项目拟制作更多的心梗模型并运用病理组织学、生物化学和分子生物学技术来系统分析Hand1的量在心肌梗死过程中的作用，揭示新的心肌梗死的病理机制,为临床预防和治疗心肌梗死提供理论指导。

Hand1是啮齿动物心脏发育中最重要的五个转录因子之一，出生后，它在心脏中表达量降低。研究发现在心梗病人中Hand1的表达量下调1/2，这一现象是否影响心梗的病程还未见报道。因此，我们的课题要研究Hand1的表达量和心梗的关系。我们用Hand1+/- 小鼠做研究对象，用同窝野生型小鼠做对照。在8-10周的公鼠左心耳下缘的冠状动脉行结扎手术从而造成小鼠心肌缺血性坏死。我们发现手术后，Hand+/-小鼠的生存率高于对照组小鼠。进一步观察发现，生存率的差别主要集中在结扎后7天内，解剖发现对照组小鼠大部分都死于心脏破裂，而Hand1+/-组小鼠心脏破裂的比例很低。通过实验分析发现Hand1+/-组小鼠在手术后金属基质蛋白酶MMP9表达量和活性都比对照组低，且凋亡细胞比对照组少。这些结果都是Hand1+/-组心脏破裂发生率低的原因。我们的研究结果表明心梗病人中出现Hand1下调是机体的保护性反应，无需治疗，为心梗的临床治疗提供了指导。