Abstract
Ischemic injury and adverse post-infarction myocardial remodeling are major causes of heart failure worldwide. Strategies designed to offset cell death with cardiomyocyte regeneration have, to date, not translated to routine clinical practice. Mir-200c modulates the transcripts of cardiogenic transcription factors (TFs) Tbx5 , Gata4 , Mef2c to promote myocyte maturation. We hypothesized that inhibition of mir-200c activity would result in postnatal myocyte de-differentiation and replication sufficient to ameliorate post-infarction decompensation after ischemic injury. To test this hypothesis, we preformed left coronary ligation on Wild-Type (WT) and transgenic mice expressing an RNA inhibitor against miR-200c ( PMIS-C ). Echocardiographic left ventricular (LV) ejection fraction (EF) fell from 88.41 ± 1.08% (WT) and 90% ± 1.42% ( PMIS-C ) (p=NS) to 28% ± 11.55% (WT) and 36% ± 9.35% at 1 day post injury (DPI) (p =NS). At 21DPI, LVEF was 27% ± 4.31% (WT) and 64% ± 4.25% ( PMIS-C ) [p ≤ 0.0001]. Post-infarction LV chamber dilation was reversed in PMIS-C mice (1.136 ± 0.19 v 0.67 ± 0.06 p ≤ 0.004 LV Vol/mass). By 9 WPI, PMIS-C heart function within non-significantly levels of sham and function prior to injury. These results indicated that inhibiting miR-200c following ischemic injury can recover cardiac function and prevent LV dilation. Moreover, trichrome stain showed a decrease in fibrosis 3 WPI (WT: 57% ± 17.46 v PMIS-C : 12% ± 3.01 p ≤ 0.001) and 9 WPI. To understand the mechanism causing this phenomenon, we analyzed expression of cardiac progenitor markers. Fold change in expression of TFs Tbx5, Gata4, Mef2c, and Isl1 were increased at 1 and 3 DPI in PMIS-C . At 1 WPI, PMIS-C border zone CMs express markers of a “progenitor-like” cell state seen during cardiogenesis. Conclusions: Inhibiting miR-200c abrogates post-infarction LV remodeling and significantly restores LV systolic function. Ongoing studies are investigating the therapeutic use of PMIS-C through delivery via AAV and nanoparticles.
Published Version
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