Qun Chu1, Anqi Li1, Xi Chen1, Ying Qin2, Xi Sun1, Yanyao Li1, Er Yue1, Cao Wang1, Xueying Ding1, Yan Yan1, Syeda Madiha Zahra2, Shuo Wang1, Yanan Jiang1, Yunlong Bai3, Baofeng Yang4. 1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150001, PR China. 2. Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China. 3. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150001, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China. Electronic address: baiyunlong@ems.hrbmu.edu.cn. 4. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150001, PR China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China; Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia. Electronic address: yangbf@ems.hrbmu.edu.cn.
Abstract
BACKGROUND: Cardiac hypertrophy is a serious factor underlying heart failure. Although a large number of pathogenic genes have been identified, the underlying molecular mechanisms of cardiac hypertrophy are still poorly understood. MicroRNAs are a class of small non-coding RNAs which regulate their target genes at the post-transcriptional level. L-type calcium channels play important role in hypertrophic signaling pathways, and CACNA1C is encoded by L-type calcium channels. Here, we hypothesize that the overexpression of miR-135b can attenuate hypertrophy by targeting CACNA1C. METHODS: We test the functional involvement of miR-135b in cardiac hypertrophy model. In order to evaluate the effect of miR-135b in cardiac hypertrophy, miR-135b mimic, miR-135b agomir and α-MHC-miR-135b transgenic mice were used for the overexpression of miR-135b. Luciferase reporter assays were used to testify the binding of miR-135b to the CACNA1C 3'UTR. RESULTS: Our results revealed that in a pathological cardiac hypertrophy model, the expression of miR-135b was clearly downregulated. Hypertrophic marker genes were upregulated after the knockdown of miR-135b in vitro, while the overexpression of miR-135b attenuated hypertrophy. These results suggested that miR-135b may weaken hypertrophic signals. We then explored the mechanism of miR-135b in hypertrophy and identified that CACNA1C was a target gene for miR-135b. The overexpression of miR-135b attenuated cardiac hypertrophy by targeting CACNA1C. CONCLUSIONS: Our studies revealed that miR-135b is a critical regulator of cardiomyocyte hypertrophy. Our findings may provide a novel strategy for the treatment of cardiac hypertrophy.
BACKGROUND:Cardiac hypertrophy is a serious factor underlying heart failure. Although a large number of pathogenic genes have been identified, the underlying molecular mechanisms of cardiac hypertrophy are still poorly understood. MicroRNAs are a class of small non-coding RNAs which regulate their target genes at the post-transcriptional level. L-type calcium channels play important role in hypertrophic signaling pathways, and CACNA1C is encoded by L-type calcium channels. Here, we hypothesize that the overexpression of miR-135b can attenuate hypertrophy by targeting CACNA1C. METHODS: We test the functional involvement of miR-135b in cardiac hypertrophy model. In order to evaluate the effect of miR-135b in cardiac hypertrophy, miR-135b mimic, miR-135b agomir and α-MHC-miR-135btransgenic mice were used for the overexpression of miR-135b. Luciferase reporter assays were used to testify the binding of miR-135b to the CACNA1C 3'UTR. RESULTS: Our results revealed that in a pathological cardiac hypertrophy model, the expression of miR-135b was clearly downregulated. Hypertrophic marker genes were upregulated after the knockdown of miR-135b in vitro, while the overexpression of miR-135battenuated hypertrophy. These results suggested that miR-135b may weaken hypertrophic signals. We then explored the mechanism of miR-135b in hypertrophy and identified that CACNA1C was a target gene for miR-135b. The overexpression of miR-135b attenuated cardiac hypertrophy by targeting CACNA1C. CONCLUSIONS: Our studies revealed that miR-135b is a critical regulator of cardiomyocyte hypertrophy. Our findings may provide a novel strategy for the treatment of cardiac hypertrophy.