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OBJECTIVE To investigate the effect and mechanism of miR-142-5p/212-5p on the proliferation and collagen formation of cardiac fibroblasts (CFs). METHODS The mouse MI model was established by ligation of the left anterior descending coronary artery. CFs were induced by transforming growth factor-beta 1 (TGF-β1) or angiotensin (Ang-Ⅱ). The molecule expressions were measured by qRT-PCR and western blot. CFs proliferation was detected by MTT assay. The effect of miR-142-5p/212-5p on the luciferase activity of c-Myc 3'-UTR was assessed by luciferase reporter assay. RESULTS miR-142-5p and miR-212-5p were down-regulated in cardiac tissues of MI mice and in TGF β1 or Ang II-induced CFs, while the protein levels of Collagen I and III were up-regulated. Moreover, simultaneous overexpression of miR-142-5p/212-5p inhibited the proliferation and collagen formation of TGF-β1- or Ang II-stimulated-CFs at a greater extent than either miR-142-5p or miR-212-5p overexpression alone. MiR-142-5p/212-5p targeted c-Myc and negatively regulated its expression. The effects of miR-142-5p/212-5p overexpression on the TP53INP1 protein level and the proliferation and collagen formation of CFs were reversed by c-Myc overexpression. Moreover, overexpression of miR-142-5p/212-5p improved cardiac function and collagen formation of MI mice. CONCLUSION Overexpression of miR-142-5p/212-5p cooperatively suppress the proliferation and collagen formation after MI by regulating c-Myc/TP53INP1.