Maternal inflammation activated ROS-p38 MAPK predisposes offspring to heart damages caused by isoproterenol via augmenting ROS generation

Abstract

Maternal inflammation contributes to the increased incidence of adult cardiovascular disease. The current study investigated the susceptibility of cardiac damage responding to isoproterenol (ISO) in adult offspring that underwent maternal inflammation (modeled by pregnant Sprague-Dawley rats with lipopolysaccharides (LPS) challenge). We found that 2 weeks of ISO treatment in adult offspring of LPS-treated mothers led to augmented heart damage, characterized by left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis. Mechanistically, prenatal exposure to LPS led to up-regulated expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, antioxidant enzymes, and p38 MAPK activity in left ventricular of adult offspring at resting state. ISO treatment exaggerated ROS generation, p38 MAPK activation but down-regulated reactive oxygen species (ROS) elimination capacity in the left ventricular of offspring from LPS-treated mothers, while antioxidant N-acetyl-L-cysteine (NAC) reversed these changes together with improved cardiac functions. The p38 inhibitor SB202190 alleviated the heart damage only via inhibiting the expression of NADPH oxidases. Collectively, our data demonstrated that prenatal inflammation programs pre-existed ROS activation in the heart tissue, which switches on the early process of oxidative damages on heart rapidly through a ROS-p38 MAPK-NADPH oxidase-ROS positive feedback loop in response to a myocardial hypertrophic challenge in adulthood.

Prenatal inflammation exposure-programmed cardiovascular diseases and potential prevention

“…Consistent with this hypothesis, our studies also demonstrated that disease conditions of myocardial remodeling (Q. Zhang, et al, 2016), hypertension and…”

“…For example, adult rat offspring with PIE at 20 weeks of age with two weeks of postnatal isoproterenol (ISO) challenge, a critical component that can activate the sympathetic nervous system and trigger stress-induced cardiomyopathy (Lymperopoulos, Rengo, & Koch, 2013), displayed augmented left-ventricular systolic dysfunction, cardiac hypertrophy and myocardial fibrosis (Q. Zhang, et al, 2016). Furthermore, the offspring with PIE at the age of 16 weeks with 4 weeks of deoxycorticosterone acetate (DOCA) and salt (DOCA-salt) treatment, an aldosterone analogue that mimicked the hyperaldosteronism-induced hypertension (Aronova, Iii, & Zarnegar, 2014), showed a…”

Transforming Growth Factor‐β Receptor III is a Potential Regulator of Ischemia‐Induced Cardiomyocyte Apoptosis

“…The MAPK signaling pathway has a well-established role in the pathogenesis of cardiovascular diseases, including MI. 11,12 The ERK1/2, JNK1/2, and p38 signaling pathways are activated in the infarcted myocardium zone and border regions upon MI. 13 Furthermore, the p38 signaling pathway is activated in the basal state in the heart, and the p38 inhibitor RWJ-67657 can restrict the infarction size in the rat following MI.…”

Reactive oxygen species‐mediated phosphorylation of p38 signaling is critically involved in apoptotic effect of Tanshinone I in colon cancer cells

“…Previous studies revealed that ROS can induce or mediate the activation of the MAPK pathways (Fang et al, 2011;Probin, Wang, & Zhou, 2007) such as activation of p38 MAPK signaling proteins leading to growth arrest and apoptosis (Hua et al, 2017;Zhang et al, 2016;J. Zhu et al, 2017).…”