The pathogenesis of hypertension-induced target organ damage is related to long-term changes in vessel function and structure. This maladaptive process of vascular remodeling is determined by genetic programs governing cell growth, programmed cell death, inflammation and matrix modulation. The set of genes that are actively expressed by the genome, the transcriptome, is a dynamic determinant of the cellular phenotype and tissue function. The proposed project will test the central hypothesis that target organ damage in hypertension is mediated by the selective up-regulation of a """"""""vasculopathic"""""""" gene profile induced by the renin-angiotensin-aldosterone system (RAAS) and is counterbalanced by an intrinsic set of """"""""vasculo-protective"""""""" genes activated by the nuclear receptor PPAR-gamma. Our experimental strategy will incorporate transgenic animals and classic pharmacologic approaches as well as DNA microarray and serial analysis of gene expression (SAGE) technologies. These analytical tools will enable us to define the vascular transcriptome during the pathogenesis of hypertension-induced target organ damage. One outcome of these studies will be the characterization of a common """"""""pharmacogenomic"""""""" profile of genes shared by therapeutic strategies that prevent target organ damage that are selectively targeted at modulating the activation of the angiotensin type I receptor, the mineralocorticoid receptor and the PPAR-gamma receptor/transcription factor.
The specific aims of the project are to: Define the vascular transcriptome associated with hypertension-induced target organ damage by establishing vascular SAGE libraries in both murine and human primary hypertension. Define the mediator role of the renin-angiotensin-aldosterone system as a """"""""vasculo-pathic"""""""" determinant of the vascular transcriptome during hypertension-induced target organ damage. Define the mediator role of PPAR-gamma as a """"""""vasculo-protective"""""""" determinant of the vascular transcriptome during hypertension-induced target organ damage.
