Activation of AMPK Attenuated Cardiac Fibrosis by Inhibiting CDK2 via p21/p27 and miR-29 Family Pathways in Rats.
Activation of AMPK Attenuated Cardiac Fibrosis by Inhibiting CDK2 via p21/p27 and miR-29 Family Pathways in Rats.
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DOI：
10.1016/j.omtn.2017.07.004
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发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Sun H
中科院分区：
文献类型：
--
作者：
Qi H;Liu Y;Li S;Chen Y;Li L;Cao Y;E M;Shi P;Song C;Li B;Sun H
心脏纤维化是几乎与所有形式的心脏病相关的病理损伤。AMP活化蛋白激酶（AMPK）是一种进化保守的能量敏感酶。越来越多的证据表明AMPK在心脏纤维化和细胞增殖中起重要作用。然而，关于AMPK激活对心脏纤维化的详细机制知之甚少。本研究发现AMPK激活可改善心肌纤维化大鼠受损的心功能，减轻心肌间质纤维化。进一步的结果表明，AMPK激活促进p21和p27的表达，抑制CDK 2和cyclin E蛋白在体内和体外的表达。此外，AMPK激活抑制下游转录因子肝细胞核因子4 α（HNF-4α）的表达，并减少HNF-4α与TGF-β1启动子的结合，最终导致TGF-β1下调和miR-29家族上调。此外，miR-29反过来通过抑制其靶点CDK 2来抑制心脏纤维化的进展。AMPK的激活一方面上调p21和p27的表达，进一步抑制CDK 2和cyclin E复合物，最终抑制心肌纤维化的进展;另一方面抑制HNF-4α的表达，进一步下调TGF-β1启动子的活性，促进miR-29的表达，最终阻止心肌纤维化的发展。
Cardiac fibrosis is pathological damage associated with nearly all forms of heart disease. AMP-activated protein kinase (AMPK) is an evolutionary conserved energy-sensing enzyme. Emerging evidences indicate that AMPK plays an important role in cardiac fibrosis and cell proliferation. However, less is known about the detailed mechanism of AMPK activation on cardiac fibrosis. In this study, we found the AMPK activation improved the impaired cardiac function of cardiac fibrosis rats and decreased interstitial fibrosis. Further results indicated AMPK activation promoted p21 and p27 and inhibited CDK2 and cyclin E protein expressions both in vivo and in vitro. Moreover, AMPK activation repressed downstream transcription factor hepatocyte nuclear factor 4 alpha (HNF-4α) expression and decreased the binding of HNF-4α to TGF-β1 promoters, which eventually resulted in TGF-β1 downregulation and miR-29 family upregulation. Furthermore, miR-29, in turn, inhibited the progression of cardiac fibrosis through suppressing its target CDK2. Taken together, activation of AMPK, on the one hand, upregulated p21 and p27 expression, further inhibited CDK2 and cyclin E complex, and finally suppressed the progression of cardiac fibrosis, and, on the other hand, repressed HNF-4α expression, further downregulated the activity of TGF-β1 promoter, promoted miR-29 expression, and finally prevented the development of cardiac fibrosis.
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