Abstract P2126: Role Of Microrna-98 In Myocardial Ischemia-reperfusion Injury In Late Pregnancy

Abstract

Background: 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. Methods: The left anterior descending coronary artery (LAD) 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. In vitro, female cardiomyocytes were transfected either miR98 mimic or inhibitor, followed by 3 hours hypoxia and 6 hours reoxygenation. Blood samples were collected from NP, LP, and coronary heart disease (CHD) patients. To assess therapeutic potential of miR, miR98 inhibitor was administered at the onset of reperfusion. 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. miR98 is significantly increased in the plasma of healthy LP compared to healthy NP women, and significantly increased in LP with CHD compared to healthy LP. 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. MiR98 overexpression in female cardiomyocytes subjected to hypoxia/reoxygenation (H/R) decreased STAT3 and PGC-1α, and increased apoptosis, inflammation, and oxidative stress, while miR-98 knockdown resulted in the opposite effect. Therapeutic targeting of microRNA-98-5p in LP rats subjected to IRI reduced infarct size, apoptosis, oxidative stress, and inflammatory markers via upregulating Stat3 and Pgc-1α. 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. Inhibition of miR-98 in LP rats reduces myocardial infarct size, apoptosis, oxidative stress, and inflammation via Stat3 and Pgc-1α.