Role of miR98 in Myocardial Ischemia Reperfusion Injury in Pregnancy - Cardiovascular disease (CVD) is the leading cause of maternal mortality, accounting for 26.5% of U.S. pregnancy-related deaths. Incidence of acute myocardial infarction (AMI) during late pregnancy (LP) used to be rare but has increased ~3.7-fold from year of 2000 to 2020 in the U.S., mainly due to rising maternal age, smoking, chronic hypertension, obesity, and diabetes. More than a decade ago, my lab was the first to report that myocardial infarct size in LP rats (day 20-21 of pregnancy) is ~4 fold greater than non-pregnant (NP) rats, however the underlying mechanisms remain unclear. Although the protective role of microRNA-98-5p (miR98) in the heart in IRI has been shown previously in male mice, our miR-microarray profiling shows for the first time, opposite to males, miR98 expression in IRI is only upregulated in the heart in LP (no change in NP, and downregulated in males), suggesting miR98 upregulation in IRI is only specific to LP and therefore could underlie higher vulnerability of the heart in LP to IRI. miR98 is an x-chromosomal linked miR and reported to be estradiol responsive in cancer cells. Our preliminary data in the heart show that miR98 is expressed in cardiomyocytes and cardiac macrophages, and its expression in both cell types are increased in LP rats upon IRI. Our pilot data also show serum from LP rat or E2 (but not progesterone) is sufficient to increase miR98 expression in female cardiomyocytes (CM). Functionally, our pilot data shows overexpression (OE) of miR98 increases apoptosis, oxidative stress, and inflammation in female CM subjected to H/R, whereas miR98 knockdown (KD) acts inhibitory. Our preliminary data show that both STAT3 and PGC1α are targets of miR98 since KD of miR98 by ~2 fold significantly increased expression of STAT3 and PGC1a, whereas ~2 fold OE of miR98 decreased expression of STAT3 and PGC1a. To assess the therapeutic potential of miR98 in IRI in LP in a clinical scenario, we administered a single dose of miR98 inhibitor at the onset of reperfusion in LP rats. Our very encouraging preliminary data show that ~2 fold downregulation of miR98 in the heart in LP was sufficient to significantly decrease the infarct size by increasing the expression of STAT3 and PGC1a. More importantly, our pilot data in LP people who had an acute MI during pregnancy and have undergone reperfusion therapy in cardiac catheterization lab (which our rat model of IRI mimics) show i) plasma miR-98 significantly increased compared to healthy LP people; and ii) plasma miR98 correlates with troponin levels. Our hypotheses are i) induction of miR98 in LP in cardiomyocytes and macrophages by estrogen leads to higher cardiac vulnerability to IRI via targeting STAT3 and PGC1α, leading to increased cell death, ROS production, and inflammation, and ii) miR98 may serve as a therapeutic modality and biomarker for prediction of MI in pregnancy and future cardiac function. Aim 1 examines the role of miR98 in cardiomyocytes and macrophages in promoting higher cardiac vulnerability to IRI in LP; Aim 2 gains mechanistic insights into the role of STAT3 and PGC1α as targets of miR98; and Aim 3 explores the translational potential of miR98 as diagnostic, prognostic, or therapeutic modality.
