Reprogramming of miR-181a/DNA methylation patterns contribute to the maternal nicotine exposure-induced fetal programming of cardiac ischemia-sensitive phenotype in postnatal life

Abstract

Background: E-cigarette and other novel electronic nicotine delivery systems (ENDS) have recently entered the market at a rapid pace. The community desperately needs answers about the health effects of ENDS. The present study tested the hypothesis that perinatal nicotine exposure (PNE) causes a gender-dependent increase in vulnerability of the heart to ischemia-reperfusion (I/R) injury and cardiac dysfunction in male rat offspring via reprogramming of the miRNA-181a (miR-181a)-mediated signaling pathway and that miR-181a antisense could rescue this phenotype. Methods: Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Cardiac function and molecular biological experiments were conducted in ~3- month-old offspring. Results: PNE enhanced I/R-induced cardiac dysfunction and infarction in adult male but not in female offspring, which was associated with miR-181a over-expression in left ventricle tissues. In addition, PNE enhanced offspring cardiac angiotensin receptor (ATR) expressions via specific CpG hypomethylation of AT 1 R/AT 2 R promoter. Furthermore, PNE attenuated cardiac lncRNA H19 levels, but up-regulated cardiac TGF-β/Smads family proteins and consequently up-regulated autophagy-related protein (Atg-5, beclin-1, LC3 II, p62) expression in the male offspring. Of importance, treatment with miR-181a antisense eliminated the PNE's effect on miR-181a expression/H19 levels and reversed PNE-mediated I/R-induced cardiac infarction and dysfunction in male offspring. Furthermore, miR-181a antisense also attenuated the effect of PNE on AT 1 R/AT 2 R/TGF-β/Smads/autophagy-related biomarkers in the male offspring. Conclusion: Our data suggest that PNE could induce a reprogramming of cardiac miR-181a expression/DNA methylation pattern, which epigenetically modulates ATR/TGF-β/autophagy signaling pathways, leading to gender-dependent development of ischemia-sensitive phenotype in postnatal life. Furthermore, miR-181a could severe as a potential therapeutic target for rescuing this phenotype.

[Retracted] Melatonin Attenuates Cardiac Ischemia‐Reperfusion Injury through Modulation of IP3R‐Mediated Mitochondria‐ER Contact

“…Furthermore, abnormal ER-mitochondria interaction impairs mitochondrial morphology and turnover, affecting normal fission/fusion cycles, and reduces mitochondrial membrane potential (MMP) to precipitate mitochondrial failure [16][17][18]. Interestingly, ER homeostasis is also compromised by deficiencies in MERCS, giving rise to ER dysfunction and the ensuing abnormal protein adaptive response [19][20][21][22]. Still, despite its potential significance for cardioprotection, the role of mitochondria-ER interaction during myocardial postischemic reperfusion damage remains incompletely understood.…”

Prenatal High‐Sucrose Diet Induced Vascular Dysfunction in Thoracic Artery of Fetal Offspring

“…Emerging evidences elicited that maternal insults could increase risks of chronic diseases later in their offspring. [ 25–29 ] Recently, many researchers pointed that prenatal malnutrition was closely linked with development of multiple organs via different mechanisms in offspring. [ 30–33 ] In the present study, we first validated that prenatal high‐sucrose diet increased maternal weight before delivery, but it had no effect on the fetal number.…”

Programming of Vascular Dysfunction by Maternal Stress: Immune System Implications

“…Although most of the data supporting deleterious effects of smoking comes from cigarette smoking, electronic cigarettes may also be important players on fetal programming ( Holbrook, 2016 ). Exposure to nicotine during intrauterine life resulted in DNA methylation of miR-181 contributing to the cardiac ischemia sensitive phenotype in adult rats, favoring autophagy signaling pathways ( Jian et al, 2020 ). AT1 and AT2 receptors gene expression in adult rat offspring from nicotine-exposed mothers is modulated by DNA methylation, eliciting high blood pressure and augmented vascular contractility in adulthood ( Xiao et al, 2014 ).…”