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Bioenergetics mitochondrial dysfunction in severe hypertensive disease in rats: role of renin angiotensin system hyperactivity

Grant number: 11/18653-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): December 01, 2011
Effective date (End): November 30, 2012
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Aníbal Eugênio Vercesi
Grantee:Camila Truzzi Penteado
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Introduction: High blood pressure (HBP), which is determined by the presence of blood pressure values above 140/90 mm Hg after 3 measures of the Office Blood Pressure (OBP) is one of the most significant cardiovascular disease (CVD) in Brazil and world, given the high rate of morbidity and mortality, intensified by the numerous risk factors and the complex pathophysiological mechanisms that contribute to this context. The treatment of hypertension is based on the use of antihypertensive drugs associated with changes in lifestyle that should be kept indefinitely. Oxidative stress, state of excessive activity of reactive oxygen species (ROS), is associated with CVD, for example, hypertensive disease (HD). In this, especially, the mitochondria can be considered a major source of ROS, especially in situations of hemodynamic and metabolic changes. There is strong evidence of the participation of the overactivity of the renin angiotensin system (RAS), especially angiotensin II (AT-II), whose excess promotes endothelial dysfunction and atherogenesis, and is also linked to vascular inflammation and myocardial lesions. It has been shown that AT-II stimulates mitochondrial dysfunction in cardiac cells and vascular smooth muscle, which leads to an overproduction of ROS's, in addition to depression of energy metabolism. Failures of the mitochondrial energy metabolism are associated with dysfunction and cell death by various causes, including CVD, as the DH, and are exemplified by: changes in transport of Ca2 +, formation of mitochondrial permeability transition pore, changes in transport of H + and K +, expression or translocation of proteins associated with apoptotic cell death and inhibition of respiratory chain components. In order to be able to relate mitochondrial bioenergetic dysfunction to RAS in the severe HD, animal (rat) models of arterial hypertension will be used, like SHR (spontaneously hypertensive rats) - in which the increase of blood pressure occurs in a progressive, and hypertension is associated with other risk factors - and RHR rats - in which overactivity of the RAS can cause hypertension, known as renovascular hypertension which, in humans, is an important cause of hypertension secondary to unilateral or bilateral stenosis of the renal artery - as well as an animal resulting from the overlapping of these two models. With this model, we intend to reproduce in rats the severe lesions observed in hypertension in humans, especially in the secondary or resistant to treatment HA. Rationale: Given the importance of hyperactivity of the RAS in the development of hypertension in humans, as well as the similarity of the pathophysiology of this disease in humans with the animal SHR, the use of overlapping of these two experimental models of hypertension in order to studying the bioenergetics of mitochondria dysfunction in myocardial and renal tissue is justified.Methodology: We will study four experimental groups of n = 12 randomly assigned to: Control (Wistar Kyoto rats), Group SHR (genetically hypertensive rats) and two groups undergoing to surgery for production of renal artery stenosis - Goldblatt technique- to induce renovascular hypertension, namely Group 2K-1C (Wistar Kyoto rats) and Group SHR/2K-1C (SHR). All animals will take water and food "ad libitum". After 4 weeks, the animals will have their morphological, biochemical and hemodynamic parameters evaluated through assessment of body weight and blood pressure tail, determination of cardiac mass, morphometric evaluations, echocardiogram, mitochondrial respiration in biopsies of cardiac muscle and renal cortex, measure of protein content and determination of carbonyl groups. For the analysis of results, analysis of variance (ANOVA) will be used for repeated measures and Bonferroni test or test Turkey post-hoc will be used to analyze the differences between the groups.