MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents
- 664 Downloads
An innovative approach for cardiac regeneration following injury is to induce endogenous cardiomyocyte (CM) cell cycle re-entry. In the present study, CMs from adult rat hearts were isolated and transfected with cel-miR-67 (control) and rno-miR-210. A significant increase in CM proliferation and mono-nucleation were observed in miR-210 group, in addition to a reduction in CM size, multi-nucleation, and cell death. When compared to control, β-catenin and Bcl-2 were upregulated while APC (adenomatous polyposis coli), p16, and caspase-3 were downregulated in miR-210 group. In silico analysis predicted cell cycle inhibitor, APC, as a direct target of miR-210 in rodents. Moreover, compared to control, a significant increase in CM survival and proliferation were observed with siRNA-mediated inhibition of APC. Furthermore, miR-210 overexpressing C57BL/6 mice (210-TG) were used for short-term ischemia/reperfusion study, revealing smaller cell size, increased mono-nucleation, decreased multi-nucleation, and increased CM proliferation in 210-TG hearts in contrast to wild-type (NTG). Likewise, myocardial infarction (MI) was created in adult mice, echocardiography was performed, and the hearts were harvested for immunohistochemistry and molecular studies. Compared to NTG, 210-TG hearts showed a significant increase in CM proliferation, reduced apoptosis, upregulated angiogenesis, reduced infarct size, and overall improvement in cardiac function following MI. β-catenin, Bcl-2, and VEGF (vascular endothelial growth factor) were upregulated while APC, p16, and caspase-3 were downregulated in 210-TG hearts. Overall, constitutive overexpression of miR-210 rescues heart function following cardiac injury in adult mice via promoting CM proliferation, cell survival, and angiogenesis.
MiRNA-210 transfected adult rat CMs show proliferation and reduced cell death in vitro.
Cell cycle inhibitor APC is a target of miR-210.
MiR-210 overexpressing (210-TG) mouse hearts show CMs cell cycle re-entry and survival post myocardial injury.
210-TG mice show significant neovascularization and angiogenic potential post myocardial infarction.
210-TG hearts show reduced infarct size following ischemic injury.
KeywordsMiR-210 Cardiomyocyte Adenomatous polyposis coli Myocardial infarction
This work was supported by the grant from National Institutes of Health (NIH) HL106190-01 to Dr. Rafeeq Habeebahmed and NIH GM103638 to Dr. Arghya Paul.
Compliance with ethical standards
All animal have been utilized in accordance with the protocol approved by the Institutional Animal Care and Use Committee (IACUC), and the studies have been performed in accordance with the ethical standards. The manuscript does not contain any clinical studies or patient data.
Conflict of interest
The authors declare that they have no conflict of interest.
- 17.Masliah-Planchon J, Pasmant E, Luscan A, Laurendeau I, Ortonne N, Hivelin M, Varin J, Valeyrie-Allanore L, Dumaine V, Lantieri L et al (2013) MicroRNAome profiling in benign and malignant neurofibromatosis type 1-associated nerve sheath tumors: evidences of PTEN pathway alterations in early NF1 tumorigenesis. BMC Genomics 14:473CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Rothe F, Ignatiadis M, Chaboteaux C, Haibe-Kains B, Kheddoumi N, Majjaj S, Badran B, Fayyad-Kazan H, Desmedt C, Harris AL et al (2011) Global microRNA expression profiling identifies MiR-210 associated with tumor proliferation, invasion and poor clinical outcome in breast cancer. PLoS One 6:e20980CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Xu HL, Xu WH, Cai Q, Feng M, Long J, Zheng W, Xiang YB, Shu XO (2009) Polymorphisms and haplotypes in the caspase-3, caspase-7, and caspase-8 genes and risk for endometrial cancer: a population-based, case-control study in a Chinese population. Cancer Epidemiol Biomark Prev 18:2114–2122CrossRefGoogle Scholar