Spiny mouse is protected from ischemia induced cardiac injury: leading role of microRNAs

and hypothesis Despite advances in drug therapy, revascularization and surgical interventions, mortality and morbidity from heart failure in ischemic heart disease remains high and a breakthrough in our understanding of this disorder is needed. Spiny mouse ( Acomys cahirinus ) has evolved a remarkable capacity to regenerate full thickness skin tissue without scarring. Here we tested the hypothesis that the lack of scarring and resulting regeneration in adult Acomys skin also applies to the heart. Methods and Results Adult Acomys and CD1 mice had either left anterior descending coronary artery ligation or sham surgery. Proliferative cells were identified by nuclear incorporation of 5‐bromodeoxyuridine (BrdU, 50mg/kg, daily, i.p.) with injections from 3d post myocardial infarction (MI) for 2wks and cardiac function was assessed by echocardiography. Following MI, Acomys infarct size was one‐fourth (18.6±3.4%) vs CD1 (76.2±3.4%, p<0.05) with 3.2 fold better systolic function (ejection fraction 77.1±6.5 vs CD1 24.6±4.6%, p<0.05). Post‐MI, Acomys had 2.2‐fold more proliferating cardiomyocytes (BrdU + cells) in their left ventricle vs CD1 mice ( Acomys ‐sham 16±9.8 vs Acomys ‐MI 101.1±30.9: CD1‐sham 11±3.5 vs CD1‐MI 44±9.1, p<0.05). We also measured the expression of miRNAs in the border zone of the infarcted hearts for both CD1 and Acomys and the corresponding zone in sham‐operated animals using small RNA‐Sequencing. We found four miRNAs that have been shown to stimulate/promote cardiomyocyte proliferation and cardiac regeneration were significantly changed in the Acomys ‐MI hearts: miR410‐3p (5.2‐fold increase in Acomys ‐MI relative to Acomys ‐Sham, Q value=<0.03), miR‐199a (miR‐199a‐3p:4.6‐fold increase in Acomys ‐MI relative to Acomys ‐Sham, Q value=0.0003; miR‐199a‐5p:3.5‐fold increase in Acomys ‐MI relative to Acomys ‐Sham, Q value=0.0088), miR‐214(miR‐214‐3p: 4.3‐fold increase in Acomys ‐MI relative to Acomys ‐Sham Q value=0.005; miR‐214‐5p: 4.0‐fold increase in Acomys ‐MI relative to Acomys ‐Sham, Q value=0.01, and let‐7f‐5p (2.0‐fold decrease in Acomys ‐MI relative to Acomys ‐Sham, Q value=0.02 <0.05). However, these miRNAs were not different between CD1 groups. Associated with this there was a dramatic increase in coronary microvasculature in the infarct region in Acomys . Conclusions We conclude that the Acomys heart responds to severe ischemia‐induced cardiac damage by increasing the number of proliferating cardiomyocytes. A possible mechanism is suggested by the upregulation of expression of microRNAs known to stimulate cardiomyocyte proliferation and cardiac regeneration (miR410, −199a, −214, let‐7f), These processes regenerated cardiac cells and vastly reduced scarring and hence preserved cardiac function. Support or Funding Information National Institute of Health grants HL33610(M.K.R), UM1 HL087366 to the Cardiovascular Cell Therapy Research Network (C.J. Pepine). Florida Heart Foundation Stop Heart Disease (Y.F. Qi).