Perinatal Epigenetic Modulation of the Brain Renin Angiotensin System Programs Cardiometabolic Diseases

Abstract

Cardiometabolic Disease (CMD) is one of the major health conditions associated with high morbidity and mortality. It is known for disturbed glycemic levels, elevated blood pressure and dyslipidemia. Epigenetic mechanisms especially DNA methylation have recently been shown to exert an essential role in the development of CMD. DNA methyltransferase (DNMT) and Ten eleven translocation (TET) are crucial enzymes controlling DNA methylation and demethylation. Pre‐autonomic neurons in the paraventricular nucleus of the hypothalamus (PVN) act as key regulators for blood pressure (BP) control. We recently reported that the renin‐angiotensin system (RAS) is an important modulator of those neurons via activation of A Disintegrin and Metalloprotease 17 (ADAM17) and Angiotensin II Type 1 receptors (AT1R) contributing to BP dysregulation. We propose that consumption of a hypercaloric diet during pregnancy leads to epigenetic modifications in the progeny’s brain, promoting autonomic dysfunction and hypersensitivity to neurogenic hypertension and metabolic disorders. In this study, C57BL6/J dams were fed a high‐fat high‐sucrose diet (HFHSD) or regular diet (RD) and mated with RD males. After weaning, offspring were put on RD for 3 months and underwent 24 h BP recording (telemetry), pharmacological assessment of autonomic function, blood glucose measurement and a glucose tolerance test before being sacrificed. RNA was extracted from the hypothalamus of HFHSD‐exposed (OH) and RD‐exposed (OR) offspring. mRNA expression for DNMT1, DNMT3a, DNMT3b, Tet1, Tet2, Tet3, AT1R and ADAM17 was quantified using real‐time PCR. Baseline BP recording showed a significant (p<0.05) and sex‐specific increase in systolic BP (140 ±2 vs. 132 ±3 mmHg) and heart rate (654 ±10 vs. 590 ±10 bpm) in OH males compared to OR controls during the active phase (6PM‐6AM). This group also exhibited significantly higher blood glucose levels (168 ±7 vs. 143 ±7 mg/dL) and sympathetic drive to the heart (Bradycardia to propranolol: −152 ±10 vs. −44 ±8 bpm). DNMT3b, Tet2, and Tet3 expression were significantly downregulated in OH mice (unpaired t‐test, p<0.05) while expression of ADAM17 and AT1R, components of the RAS, were upregulated (p=0.002 and 0.005, respectively). To elucidate the mechanisms involved in future experiments, an in vitro model was developed using N2A cells treated with a glucose‐lipid mixture and validated by the significant downregulation of gene expression for DNMT1, DNMT3a (p<0.01), Tet1, Tet3 (p<0.05) in comparison to untreated N2A cells. We conclude that consumption of HFHSD during pregnancy promotes changes in methylation profiles within the hypothalamus, leading to altered gene expression, notably of RAS genes in the brain, which in turn could trigger autonomic dysfunction and hypersensitivity to cardiometabolic disease.Support or Funding InformationAmerican Diabetes Association (1‐19‐IBS‐291), Veterans Affairs Merit Award (BX004294), National Institutes of Health (HL093178 and COBRE P30GM106392), and LSUHSC‐NO Research Enhancement Program.