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Published on: June 3, 2018
Targeting miR-30d reverses pathological cardiac hypertrophy
Jin Li1, Zhao Sha1, Xiaolan Zhu1
1Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China.
Insights
MicroRNA-30d (miR-30d) levels decrease in pathological cardiac hypertrophy. Restoring miR-30d ameliorates cardiac hypertrophy by targeting key genes and pathways, offering a potential therapeutic strategy for heart failure.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Biochemistry
Background:
- Pathological cardiac hypertrophy is a precursor to heart failure (HF).
- Effective therapies for pathological cardiac hypertrophy are urgently needed.
- MicroRNAs play crucial roles in regulating cardiac function and disease.
Purpose of the Study:
- To investigate the role of miR-30d in pathological cardiac hypertrophy.
- To elucidate the molecular mechanisms underlying miR-30d's function in cardiac hypertrophy.
- To evaluate the therapeutic potential of miR-30d in treating cardiac hypertrophy and HF.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) to measure miR-30d expression in hypertrophy models and patient serum.
- In vitro and in vivo gain- and loss-of-function experiments for miR-30d.
- Bioinformatics, western blot, luciferase assays, and immunofluorescence to determine molecular mechanisms.
Main Results:
- miR-30d expression was significantly decreased in cardiac hypertrophy models and chronic heart failure patients.
- Overexpression of miR-30d attenuated hypertrophy induced by phenylephrine (PE) and angiotensin II (Ang II) in cardiomyocytes.
- miR-30d protected against isoproterenol (ISO)-induced cardiac hypertrophy in transgenic rats and ameliorated hypertrophy in human cells.
Conclusions:
- miR-30d acts as a protective microRNA against pathological cardiac hypertrophy.
- miR-30d functions by inhibiting pro-hypertrophic pathways, including NFAT signaling, via targeting MAP4K4 and GRP78.
- Restoring miR-30d levels, potentially via adeno-associated virus (AAV) vectors, represents a promising therapeutic strategy for cardiac hypertrophy and heart failure.
Background:
Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed.
Methods:
The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d.
Findings:
miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes.
Interpretation:
Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy.
Funding:
This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).
