Activation of AMPK Attenuated Cardiac Fibrosis by Inhibiting CDK2 via p21/p27 and miR-29 Family Pathways in Rats

作者：Qi, Hanping; Liu, Yan; Li, Shuzhi; Chen, Yunping; Li, Lei; Cao, Yonggang; E, Mingyao; Shi, Pilong; Song, Chao; Li, Baiyan; Sun, Hongli^*

来源：Molecular Therapy - Nucleic Acids, 2017, 8: 277-290.

DOI：10.1016/j.omtn.2017.07.004

• ACETYL-COA CARBOXYLASE
• PROTEIN-KINASE
• CELL-CYCLE
• HEART
• HYPERTROPHY
• REPERFUSION
• MICRORNAS
• MECHANISM
• ISCHEMIA
• STRESS

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-4 alpha) expression and decreased the binding of HNF-4 alpha to TGF-beta 1 promoters, which eventually resulted in TGF-beta 1 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-4 alpha expression, further downregulated the activity of TGF-beta 1 promoter, promoted miR-29 expression, and finally prevented the development of cardiac fibrosis.

• 出版日期2017-9-15
• 单位哈尔滨医科大学