Factors that accumulate with age such as increased sodium intake have been linked to age-associated vascular dysfunction, increased blood pressure and the onset of cardiovascular diseases. However, the mechanisms that mediate interaction between environmental factors such as dietary salt intake and an individual's genetic background resulting in age-associated blood pressure increases are unclear. This supplemental application is a Revision to a recently funded proposal focused on the characterization of a newly identified association between striatin, a caveolin-1 binding protein, and two factors: aldosterone (ALDO)'s mechanisms of action and vascular function. We have recently documented that striatin is a key intermediate in: 1) ALDO's non-genomic mechanism of action; 2) the blood pressure response to sodium intake in humans and mice; and 3) . polymorphic variants of the striatin gene are associated with salt sensitive hypertension in humans. Also, our Preliminary Results show that 1) young male striatin heterozygous knockout mice (STRN+/-) have increased Na+ sensitive blood pressure and altered vascular vasodilator responses that are associated with reduced striatin levels; 2) but, young female STRN+/- mice do not appear to have Na+ sensitive blood pressure even though they have reduced striatin levels. 3) However, female STRN+/- but not female wild type (WT) mice have an age-related trend to Na+ sensitive blood pressure. These data suggest that striatin: 1) is a novel key modulator of ALDO's mechanisms of action; 2) is likely an important modulator of vascular function; and 3) variation in striatin gene expression may in part mediate vascular responses to changes in salt intake that are likely potentiated by aging. Consequently, as age and high dietary salt intake are predictors of hypertension, we hypothesize that striatin modulates the interaction of age and salt intake on blood pressure. These novel findings provide entre to this proposal that focuses on studying aged mice in order to conduct age-based analyses. Our goals will be assessed through the following Aim: 1) To test the hypothesis that in mice, age and striatin interact to modify aldosterone and vascular responses to changes in Na+ intake. These novel studies will take advantage our recently characterized mouse model of reduced striatin levels to perform three series of studies in 18 month old mice and 1) characterize the blood pressure responses to Na+ intake in STRN+/- male and female mice; 2) isolate the aortas from these mice and characterize the effects of aortic responses to acetylcholine and phenylephrine; and 3) study primary aortic endothelial cells isolated from these mice to characterize the direct effects of ALDO in these cells. These studies are significant as they will address how striatin may modify aging and aging-related processes that affect the progression of a chronic disorder such as hypertension.
Striatin is a protein that interacts with important receptors within cells that regulate the function of the heart and blood vessels. Striatin deficiency impairs the ability of vessels to respond appropriately to steroids like aldosterone and estrogen. This project will assess the role of aging on the mechanisms by which striatin and dietary salt can lead to changes in blood pressure and blood vessel function.
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