Abstract P1081: Inhibition Of Mir-200c Abrogates Post-infarction LV Remodeling Following A Myocardial Infarct.

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. m ir-200c modulates the transcripts of cardiogenic transcription factors (TFs) Tbx5 and Gata4 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 (I-200c). Echocardiographic left ventricular (LV) ejection fraction (EF) fell from 88.41 ± 1.08% (WT) and 90% ± 1.42% (I-200c) (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% (I-200c) [p ≤ 0.0001]. Post-infarction LV chamber dilation was inhibited in I-200c mice (1.136 ± 0.19 v 0.67 ± 0.06 p ≤ 0.004 LV Vol/mass). 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 21 DPI (WT: 57% ± 17.46 v I-200c: 12% ± 3.01 p ≤ 0.001). To understand the mechanism causing this phenomenon, we analyzed expression of cardiac progenitor markers Tbx5 and Gata4 . Fold change in expression of both TFs were increased at 21 DPI (WT: 1.02 ± 0.09 v I-200c: 2.86 ± 0.76 p ≤ 0.05; WT: 1.00 ± 0.02 v I-200c: 3.08 ± 0.64 p ≤ 0.05). Additionally, I-200c mice have increased fold change of the cardiac progenitor factor Nkx2.5 (1.01 ± 0.07 v 4.16 ± 1.08 p ≤ 0.05). Tbx5, Gata4, Nkx2.5, in the context of ischemic injury, are thought to perturb post-infarct remodeling and promote CM survival. Conclusions: I-200c treatment abrogates post-infarction LV remodeling and significantly restores LV systolic function, which are associated with increased myocyte expression of cardiogenic progenitor markers. Future studies will determine the importance of myocyte proliferation vs. humoral modulation of surviving myocyte phenotype, toward protection of post-infarction LVs.