Abstract
Background: Myocardial infarction (MI) is caused by occlusion of the coronary artery and induces ischemia in the myocardium and eventually a massive loss in cardiomyocytes. Studies have shown many factors or treatments that can affect the healing and remodeling of the heart upon infarction, leading to better cardiac performance and clinical outcome. Previously, miR-132/212 has been shown to play an important role in arteriogenesis in a mouse model of hindlimb ischemia and in the regulation of cardiac contractility in hypertrophic cardiomyopathy in mice. In this study, we explored the role of miR-132/212 during ischemia in a murine MI model.Methods and Results: miR-132/212 knockout mice show enhanced cardiac contractile function at baseline compared to wild-type controls, as assessed by echocardiography. One day after induction of MI by permanent occlusion, miR-132/212 knockout mice display similar levels of cardiac damage as wild-type controls, as demonstrated by infarction size quantification and LDH release, although a trend toward more cardiomyocyte cell death was observed in the knockout mice as shown by TUNEL staining. Four weeks after MI, miR-132/212 knockout mice show no differences in terms of cardiac function, expression of cardiac stress markers, and fibrotic remodeling, although vascularization was reduced. In line with these in vivo observation, overexpression of miR-132 or miR-212 in neonatal rat cardiomyocyte suppress hypoxia induced cardiomyocyte cell death.Conclusion: Although we previously observed a role in collateral formation and myocardial contractility, the absence of miR-132/212 did not affect the overall myocardial performance upon a permanent occlusion of the coronary artery. This suggests an interplay of different roles of this miR-132/212 before and during MI, including an inhibitory effect on cell death and angiogenesis, and a positive effect on cardiac contractility and autophagic response. Thus, spatial or tissue specific manipulation of this microRNA family may be essential to fully understand the roles and to develop interventions to reduce infarct size.
Highlights
The mortality rate of myocardial infarction (MI) in patients is going down due to recently developed post-infarction treatments and secondary prevention, MI is still one of the leading causes of mortality (Mozaffarian et al, 2015). 12.5% of patients that suffered a MI with ST-segment elevation may die within 6 months (Steg et al, 2012), suggesting that novel effective treatments are still required.microRNAs are small non-coding RNAs that play essential roles in cardiac development, and dysregulation of microRNAs promote the pathological progression of many cardiac diseases
For assessing the role of miR-132/212 in the setting of an acute MI, Left anterior descending artery (LAD) ligations were performed in miR-132/212 knockout and WT control mice Figure 2A. 24 h post-MI, cardiac damage was assessed by TTC staining on cardiac slices from operated WT and KO mice (Figure 2B)
No significant differences were observed in infarct size (IS), as measured both in the percentage of LV (IS/LV) and in the percentage of area at risk (IS/AAR)
Summary
The mortality rate of myocardial infarction (MI) in patients is going down due to recently developed post-infarction treatments and secondary prevention, MI is still one of the leading causes of mortality (Mozaffarian et al, 2015). 12.5% of patients that suffered a MI with ST-segment elevation may die within 6 months (Steg et al, 2012), suggesting that novel effective treatments are still required.microRNAs are small non-coding RNAs that play essential roles in cardiac development, and dysregulation of microRNAs promote the pathological progression of many cardiac diseases. The miR-132/212 family plays essential roles in maintaining physiological function and pathological disease progression of the cardiovascular system. Loss of miR132/212 shows impaired angiogenesis response in hindlimb ischemia model (Lei et al, 2015) and overexpression of miR132/212 enhance neovascularization. They are reported to be upregulated in the failing human heart, where they play a detrimental role in the regulation of cardiomyocyte contractility and the cardiac hypertrophy in hypertension-induced heart failure models (Ucar et al, 2012). MiR-132/212 has been shown to play an important role in arteriogenesis in a mouse model of hindlimb ischemia and in the regulation of cardiac contractility in hypertrophic cardiomyopathy in mice. We explored the role of miR-132/212 during ischemia in a murine MI model
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
