Evaluation of epigenetic mechanisms in response to drug treatments in genes related to Hypertension in an experimental animal model

Abstract

It is recent the knowledge that epigenetic reprogramming can occur in adulthood, impacting the course of certain diseases. Key genes play an essential role in the functioning and maintenance of the cardiovascular system, since the deletion of some of them, such as NOS3, which expresses the endothelial Nitric Oxide Synthase (eNOS) gene, responsible for synthesizing most of the Nitric Oxide in vessels, can lead to systemic and pulmonary arterial hypertension, abnormal vascular remodeling, defective and pathological angiogenesis and even defective healing. It has been observed that especially the methylation of the promoter region of genes leads to their "silencing". With these mechanisms in mind, there are drugs that can act to modulate this pathway. Thus, this project aims to evaluate the effects of pharmacological treatments on the regulation of epigenetic mechanisms in specific genes of cardiovascular relevance and inflammatory process in a hypertensive animal model, with two hypotheses: 1) Hypertension will induce changes in the methylation process of specific genes (NOS3, SOCS1, MMPs 2 and 9), changing the gene expression in a time-dependent course, contributing to cardiac morphological and vascular functional changes; 2) the pharmacological treatment (atorvastatin and 5' azacitidine) will modify the methylation framework of the specific genes studied, restoring vascular function and cardiac morphology, decreasing the levels of inflammatory markers in a hypertensive animal model. For this, wistar hannover rats with 2K1C model (Goldblatt model) will be used to induce hypertension. The vascular functioning will be evaluated through aortic vascular reactivity and cardiac morphology to relate them to epigenetic alterations, such as DNA methyltransferase 1 (DNMT 1) activity, methylation of the promoter region of specific genes and gene expression. (AU)