UCLA

Maternal mortality remains high in the US and pregnancy-associated myocardial infarction accounts for over 20% of maternal cardiac deaths. The relative risk of myocardial infarction during pregnancy is approximately 3 to 4-fold higher than the rates of age-matched non-pregnant individuals in the reproductive age group. During myocardial infarction, ischemia restricts blood flow to the myocardium, necessitating timely reperfusion therapy to restore blood flow. However, reperfusion therapy can exacerbate tissue damage. Our lab has demonstrated that cardiac vulnerability to ischemia reperfusion injury drastically increases in late pregnancy, and one bolus of intralipid at reperfusion reduces the infarct size in late pregnant rats. However, the mechanisms underlying the higher vulnerability of late pregnancy to ischemia reperfusion injury and the cardioprotective role of intralipid are unknown. In Chapter 2, we employ a rat model to investigate the reasons behind the heightened susceptibility of the heart in late pregnancy to ischemia-reperfusion injury. We identify microRNA-98-5p, whose expression increases during late pregnancy upon ischemia reperfusion injury, and promotes cardiomyocyte apoptosis, mitochondrial oxidative stress, and inflammation via its targets Stat3 and Pgc-1α. In an in vivo late pregnant ischemia-reperfusion injury rat model, we show the therapeutic potential of microRNA-98-5p inhibition at the onset of reperfusion. In late pregnant patients with acute myocardial infarction, plasma microRNA-98-5p was significantly higher than healthy late pregnancy and it was correlated with troponin levels. In Chapter 3, we study the therapeutic role of intralipid in attenuating ischemia-reperfusion injury in a rat model of late pregnancy. We demonstrate that the protective effects of intralipid are mediated by microRNA-122-5p. MicroRNA-122-5p exhibits its protective effects in late pregnancy by mitigating cardiomyocyte apoptosis and oxidative stress through its target Pkm2. In humans, plasma microRNA-122-5p levels were lower in healthy late pregnant compared to healthy non-pregnant individuals and even lower in late pregnant patients with acute MI and negatively correlated with troponin levels. In an in vivo late pregnant ischemia-reperfusion injury rat model, we show the therapeutic potential of microRNA-122-5p overexpression at the onset of reperfusion. Taken together, this dissertation offers insights into the heightened susceptibility of late pregnancy to ischemia-reperfusion injury and the cardioprotective role of intralipid.