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Effects of drugs activating the NO-cGMP pathway on the production of MMPs in cell culture

Grant number: 13/09930-0
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): July 20, 2013
Effective date (End): January 19, 2014
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal researcher:Fernando Morgan de Aguiar Correa
Grantee:Danielle Aparecida Guimarães
Supervisor abroad: Sruti Shiva
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: University of Pittsburgh (Pitt), United States  
Associated to the scholarship:10/15861-3 - Effects of drugs activating NO-cGMP pathway in vascular changes associated with experimental hypertension 2R1C, BP.DR

Abstract

Cardiovascular diseases such as hypertension are associated with increased activation of matrix metalloproteinases (MMPs). MMPs are calcium-dependent endopeptidases, expressed in various cells and tissues including vascular smooth muscle cells, endothelial cells, fibroblasts and inflammatory cells. These enzymes can be regulated by various processes, and an increase in activation of these proteases, promotes excessive degradation of extracellular matrix components and thereby causes a pathological vascular remodeling. Statins reduce cholesterol production, and as sildenafil, which is widely used in the treatment of erectile dysfunction and is an inhibitor of phosphodiesterase (PDE5), has beneficial effects called pleiotropic effects. Among these effects include: the improvement in endothelial function, reduction in blood pressure, increased nitric oxide (NO) bioavailability and antioxidant effects. Among the results of the PhD project development we observed that atorvastatin and sildenafil inhibits vascular remodeling induced by 2K1C hypertension because they reduce the expression / activity of MMP-2 in the aorta and reduce oxidative stress that is capable of inducing the activity of these enzymes. However, it was not evaluated yet the effect of these drugs on MMPs in cultured smooth muscle cells and endothelial cells, including MMP-9 which was regarded as a marker of cardiovascular risk. The objective of this project is to determine the effect of atorvastatin and sildenafil alone or in combination on MMPs (2 e 9) in vascular cells, in order to confirm and complement the results found in vivo. (AU)