Key result
CircMap4k2 overexpression attenuates post-SVR cardiac remodeling via miR-106a-3p/Azin1-driven proliferation.
Why the study?
Residual remodeling limits HF improvement after SVR, and whether circRNAs and enhanced endogenous cardiomyocyte regeneration further improve HF remained unclear.
CircMap4k2 acts as a key mediator of cardiomyocyte regeneration after surgical ventricular reconstruction, offering a potential therapeutic target to further attenuate residual cardiac remodeling in post-MI heart failure.
Should not change post-MI surgical practice; leaves open CircMap4k2 modulation as a regeneration target in humans.
INTRODUCTION: Surgical ventricular reconstruction (SVR) is an alternative therapeutic approach in patients with refractory heart failure (HF), but residual remodeling after SVR limits the improvement of HF. Recently, we reported that SVR may act as an environmental cue to reactivate endogenous proliferation of cardiomyocytes; however, it is unclear whether enhancing endogenous cardiomyocyte regeneration further improves HF after SVR. OBJECTIVES: We aimed to explore whether circular RNAs (circRNAs) would involved in SVR and their mechanisms. METHODS: Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with a large ventricular aneurysm underwent SVR or a second open-chest operation only. Echocardiography and histological analysis were used to evaluate heart function, cardiac remodeling, and myocardial regeneration. Sequencing of circular RNAs, RNA immunoprecipitation, RNA pulldown, and luciferase reporter assay were used to explore the underlying mechanisms. RESULTS: SVR markedly attenuated cardiac remodeling and induced cardiomyocyte regeneration, as evidenced by positive staining of Ki-67, phospho-histone H3 (pH3), and Aurora B in the plication zone, but significant residual remodeling still existed in comparison with the sham group. Sequencing results showed that SVR altered the expression profile of cardiac circRNAs, and circMap4k2 was identified as the most upregulated one. After characterizing circMap4k2, we noted that overexpression of circMap4k2 significantly promoted proliferation of cardiomyocytes in cultured neonatal rat cardiomyocytes and silencing of circMap4k2 significantly inhibited it; similar results were obtained in SVR-treated MI mice but not in MI mice without SVR treatment. Residual cardiac remodeling after SVR was further attenuated by circMap4k2 overexpression. CircMap4k2 bound with miR-106a-3p and inhibited cardiomyocyte proliferation by targeting a downstream effector of the antizyme inhibitor 1 (Azin1) gene. CONCLUSIONS: CircMap4k2 acts as an environmental cue and targets the miR-106a-3p/Azin1 pathway to increase cardiac regeneration in the plication zone and attenuate residual remodeling after SVR.
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Yan et al. (2023) studied Myocardial infarction and heart failure. Surgical ventricular reconstruction (SVR) and circMap4k2 overexpression vs. Sham surgery or MI without SVR was evaluated on Heart function, cardiac remodeling, and myocardial regeneration. CircMap4k2 overexpression further attenuated residual cardiac remodeling after surgical ventricular reconstruction by promoting cardiomyocyte proliferation via the miR-106a-3p/Azin1 pathway.
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