This is a translational research proposal focused on a newly identified association between striatin and two factors: aldosterone's mechanisms of action and vascular function. Striatin is a cytosolic protein that has been reported to be a criticl intermediate in estrogen's non-genomic mechanism of action. Recently, we have documented that striatin: 1) is present in several cardiovascular tissues, mononuclear cells and the adrenal cortex;2) is an important regulator of aldosterone's non-genomic mechanism of action in human vascular endothelial and mononuclear cells;3) is regulated by aldosterone and the level of sodium intake;4) gene polymorphic variants are associated with salt sensitive hypertension in humans. These data suggest that striatin is a key modulator of aldosterone mechanisms of action and likely an important modifier of vascular function. Furthermore, variation in striatin gene expression may be involved in mediating vascular responses to changes in salt intake, potentially related to striatin's role in mediating aldosterone's mechanism of action and/or secretion. These novel findings provided entr?e to several avenues for future studies. However, this proposal will focus only on two of them: 1) determining striatin's role in modulating vascular and cardiac function and 2) assessing striatin's role in mediating aldosterone biosynthesis. These two goals will be assessed in Three SPECIFIC AIMS using a three-level translational approach - humans, genetically modified animals, and cells. First, we will test the hypothesis that in hypertensives, striatin status is an important mediator of vascular function and vascular responses to changes in Na+ intake and aldosterone secretion. Second, in mononuclear cells from hypertensives we will test three hypotheses related to the predictability of striatin gene variants on: 1) striatin levels;2) non-genomic and striatin protein responses to aldosterone and estrogen;and 3) striatin protein responses to Na+ intake. Third, we will test the hypothesis that in genetic modified mice and cells, striatin gene status is an important mediator of vascular function, vascular responses to changes in sodium intake and aldosterone secretion. These goals will be accomplished by assessing in striatin+/+ and striatin+/- mice, placed on a liberal or a Na+ restricted diet: 1) BP;2) ex vivo aortic functional studies;3) in vitro molecular studies i cardiac, vascular and adrenal tissue;4) molecular studies in primary endothelial cell cultures and 5) mononuclear cells. Studies in a human adrenal cell line will assess more directly striatin's role in regulating aldosterone secretion. Thus, completing the proposed aims of this project, will define how striatin influences cardiovascular function, its interaction with sodium intake and aldosterone and may provide entr?e to valuable new approaches to prevent and/or treat hypertension and its consequences.
Striatin is a protein that interacts with important receptors involved in signaling mechanisms inside cells that regulate the function of the heart and blood vessels. Striatin deficiency impairs the ability of vessels to respond appropriately to steroids lie aldosterone and estrogen. This project will assess the mechanisms by which genetic variation in striatin can lead to changes in heart and blood vessel function in people with high blood pressure.
|Coutinho, Patricia; Vega, Christopher; Pojoga, Luminita H et al. (2014) Aldosterone's rapid, nongenomic effects are mediated by striatin: a modulator of aldosterone's effect on estrogen action. Endocrinology 155:2233-43|