Abstract 12920: Mir98 Regulates Myocardial Ischemia-Reperfusion Injury in Late Pregnancy by Targeting Stat3 and Pgc-1α

Abstract

INTRODUCTION: We have shown that the late-pregnant (LP) rodent is more vulnerable to myocardial ischemia-reperfusion injury (IRI) compared to non-pregnant (NP). The molecular mechanisms are unknown. Several microRNAs (miRs) are dysregulated in IRI, making them promising therapeutic targets. Our goal is to decipher the mechanisms underlying the higher susceptibility of LP to IRI. Methods: The left anterior descending coronary artery of female Sprague-Dawley rats (2-3 months old NP and LP, 20-21 days pregnant) was occluded for 45 minutes followed by 3 hours reperfusion. Myocardial necrosis was assessed using TTC staining. MicroRNA-microarray profiling was performed on hearts of NP and LP rats subjected to IRI (Ocean Ridge Biosciences). In vitro, female cardiomyocytes were transfected either miR98 mimic or inhibitor (40uM), followed by 3 hours hypoxia and 6 hours reoxygenation. Human blood samples were collected from NP, LP, and coronary heart disease (CHD) patients. Data were expressed as mean±SEM. P<0.05 was considered statistically significant. Results: MicroRNA-microarray profiling revealed miR-98-5p (miR-98) is upregulated in the hearts of LP IRI rats compared to NP IRI by 2.3 folds, which we confirmed with qPCR (1.89±0.15, n=5 animals/group). miR98 is significantly increased in the plasma of healthy LP compared to healthy NP women (2.32±0.44, LP n=9, NP n=7), and significantly increased in LP with CHD compared to healthy LP (4.41±0.73, CHD n=5). TargetScan revealed STAT3 and PGC-1α to be targets of miR98. We confirmed significantly decreased expression of STAT3 and PGC-1α in LP IRI rat myocardium compared to NP IRI (STAT3 0.48±0.12 n=5 and PGC-1α 0.39±0.17 n=5). MiR98 overexpression in female cardiomyocytes subjected to hypoxia/reoxygenation (H/R) significantly decreased STAT3 (0.75±0.11) and PGC-1α (0.52±0.16), and increased apoptosis (1.89±0.09), inflammation (2.12±0.18), and oxidative stress (2.3±0.22), while miR-98 knockdown resulted in the opposite effect (n=4). Conclusions: MiR98 is upregulated in LP rats subjected to IRI compared to NP IRI and in LP human plasma samples with CHD compared to healthy NP and LP. miR98 promotes oxidative stress, inflammation, and apoptosis in the setting of H/R in vitro by targeting STAT3 and PGC-1α.