Utilization of ruthenium complex as pharmacological strategy to revert and/or prevent the endothelial dysfunction

Abstract

The endothelial dysfunction has been considered as an indicator of cardiovascular diseases, considering that low nitric oxide (NO) bioavailability contributes to development and progression of hypertension and atherosclerosis, which can induces cardiac and cerebral ischemic diseases. The endothelial dysfunction is mainly characterized by decrease on capacity of endothelial cells to release NO. The NO has a couple of beneficial physiologic effects, including: modulation of vascular tonus, inhibition of platelet aggregation, decreases the expression of adhesion molecule, decreases vascular smooth muscle cells proliferation and induces a anti-inflammatory effect by PPARg activation and NF-kB inhibition. The NO is a radical specie and reacts rapidly with other molecules that have unpaired electron, being extremely unstable under physiological conditions. The superoxide anion (O2-) decreases the NO bioavailability and activates NF-ºB, an important pro-inflammatory transcription factor, which has been found activated in cells from cardiovascular system in the presence of cardiovascular diseases, including: hypertension, atherosclerosis and heart failure. Thus, the decrease of NF-ºB activity induced by NO and by O2- scavenging can be a good strategy on prevention and/or reversion of cardiovascular diseases. In previous studies we have verified that the ruthenium complex cis-[Ru(H-dcbpy-)2(Cl)(NO)] and cis-[Ru(bpy)2(NO2-)(NO)](PF6)2 actuate as a NO donors and the compound cis-[Ru(H-dcbpy-)2(Cl)(NO)] inactivate the O2- generated by xantine oxidase. This way, our hypothesis is that these compounds can revert and/or prevent the endothelial dysfunction. This effect could normalize the blood pressure, decrease the risk of development of cardiac and cerebral ischemic diseases and heart failure. To test our hypothesis, the hypertension animal model two kidney one clip (2K-1C) and endothelium cells in culture stimulated with angiotensin II will be used, considering that in these conditions will be possible to get dysfunctional endothelial cell with high O2- concentration. The principal aim of this study will be to test our hypothesis and proceed the pharmacological characterization of dependent effects of O2- scavenging and NO release induced by these ruthenium compounds. This project will allow the implantation of an emergent research area on Centro de Ciências Biológicas e da Saúde (CCBS), from Departamento de Ciências Fisiológicas (DCF). The DCF shows a good structure on Cellular Biology, Biochemistry and Endocrinology, which will be available for the development of this project through established collaborations with teachers of this department. Also, this project will have the collaboration of Profa. Dr. Lusiane M. Bendhack and Prof. Dr Roberto S. Da Silva, both from Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP. (AU)