Proteomic Analysis of the Hypertensive Phenotype in Rats
Proteomics , Sontaneously Hypertensive Rat , Hypertension
Hypertension is a major risk factor for developing cardiovascular, renal and nervous system pathologies. Refractory hypertension is prevalent at approximately 30% despite diet, lifestyle and multiple pharmacologic interventions. Blood pressure can be influenced at the level of the nervous system, at the level of the kidney, and at the level of the vasculature. This document describes investigations performed into each of these systems during the development of hypertension using a model of human essential hypertension, the spontaneously hypertensive rat (SHR), by a proteomic approach of 2-dimensional gel electrophoresis and mass spectrometry. A transgenic mouse model with deficits in p75 neurotrophin receptor (NTR), which has been implicated in hypertension, was similarly investigated. Proteomics is a scientific strategy that is not entirely hypothesis driven, rather it has the hypothesis that functional and phenotypic changes in pathophysiology are reflected at the protein level. Proteomics compares the proteome of a disease state, treatment, temporal state, to an appropriate control to determine changes in the level of protein present and its biochemical properties. Proteome changes in the SHR mesenteric arteries included the novel observation of increased CLIC1 association with the adventitia in the SHR, the decreased expression of HSP90 alpha and beta in the SHR, and the presence of an additional protein spot for tropomyosin beta and MLC20 in the SHR. These proteome changes are suggestive of an increased contractile state in the mesenteric resistance arteries of SHR. In the renal proteome, there was a decrease of alpha-2μ globulin and a decrease in MAWDBP in the SHR demonstrating molecular changes in the kidney before known pathological changes. In superior cervical ganglia, sstereological measurement showed significant increases in the number of sympathetic neurons in both lines of p75NTR-deficient mice, relative to wild type mice with an enhanced survival of sympathetic neurons associated with shifts toward the more basic isoforms of Annexin V in the proteomes of p75NTR-deficient mice.