Abstract 21380: RBM39 is Vital for Maternal Obesity-Induced Fetal Sheep Cardiac Contractile Dysfunction by Regulating Myocardial Autophagy

Abstract

Maternal obesity becomes pandemics in 21 st century. Previous epidemiological studies on humans suggested that obesity during pregnancy could result in increased incidences of cardiovascular diseases in the offspring. Studies on animal models also indicated that maternal obesity could induce cardio dysfunction in offspring. However, the mechanisms underlying are still not well elucidated. Previously we have reported that maternal obesity could lead to fetal cardiac contractile dysfunction in sheep. Moreover, from mid- to late-gestation, the cortisol level has been shown increased in fetuses born from obese ewes. Here, we are trying to tie the relationship of upregulated cortisol level in fetuses to maternal obesity-induced fetal cardiac contractile dysfunction. We found that RBM39, a critical transcriptional factor which is activated by hormonal stimulation, was 2.5-fold upregulated in fetal myocardium from obese ewes. Moreover, maternal obesity induced autophagic gene upregulation in fetal myocardium. Meanwhile, the expression of the autophagic cargo protein SQSTM1, also known as ubiquitin-binding protein p62, is also upregulated in maternal obesity fetal hearts. The upregulated SQSTM1 is an indicator of blockade of autophagic flux. Collectively, our studies reveal RBM39 as a transcriptional factor, is activated by increased levels of cortisol in fetuses from mid- to late-gestation. In turn, autophagy pathways have been activated via RBM39 transcriptional regulation in fetal myocardium of fetuses born from obese ewes, as well as the autophagy cargo protein SQSTM1. Therefore, the autophagic flux has been disturbed in the myocardium of fetuses born from obese ewes, which could be a possible mechanism of maternal obesity-induced cardiac contractile dysfunction.