This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this study, we will test the hypothesis that genetic variation in CYP11B2 modulates aldosterone synthesis in response to stimulation by Ang II and potassium in hypertensive African Americans and Caucasians. The effect of racea nd salt-sensitivity on genetic variation in CYP11B2 will also be determined.
SPECIFIC AIMS : Genetic variation in the renin-angiotensin-aldosterone system (RAAS) contributes to the development of hypertension and cardiovascular and renal morbidity, complications more prevalent in African Americans than other ethnic groups. Variants of the genes encoding for angiotensinogen (AGT) and angiotensin converting enzyme (ACE) are associated with ypertension and target organ damage. Mechanisms by which genetic variants in the RAAS increase target organ damage are not certain but have largely been attributed to effects of angiotensin (Ang II), which has well-described effects on vascular tone, cellular growth and proliferation. Emerging data suggest that aldosterone plays an independent role in vascular toxicity. In animal and human studies, elevated plasma aldosterone (aldo) is associated with endothelial dysfunction, vascular and cardiac hypertrophy, and salt-dependent secondary hypertension. Aldosterone, a mineralocorticoid, acts to enhance sodium reabsorption, potassium excretion, and extracellular volume expansion. In addition aldosterone causes myocardial and vascular fibrosis. Biosyntehsis of aldosterone in adrenal and extraadrenal sites depends on the activity of a cytochrome P450 enzyme, CYP11B2, also known as aldosterone synthase. Recent studies suggest that CYP11B2 is the focal point of aldosterone regulation by potassium and Ang II, the predominant physiologic regulators of aldo. A common diallelic (C/T) polymorphism at position -344 in the promoter of CYP11B2 has been associated with increased basal aldosterone, increased adrenocorticotropic hormone (ACTH)-stimulated 11-deoxycortisol, and hypertension in studies done in Caucasians. In preliminary studies, we have demonstrated a significant increase in aldosterone synthesis in response to Ang II in normotensive subjects homozygous for CYP11B2 -344 T compared to those with either -344 CT or -344 CC. Previously Fisher et al. compared adrenal responsiveness among African Americans and Caucasians and found that in hypertensive but not normotensive subjects, the increase in plasma aldosterone was blunted in African Americans. In a group of hypertensive Caucasians who had demonstrated decreased plasma aldosterone responsiveness to Ang II compared to normotensive controls, Dawson-Hughes et al. showed that plasma aldosterone responsiveness to potassium was similarly decreased.
SPECIFIC AIMS : 1.) To determine the effect of genetic variation in CYP11B2 on the increase in aldosterone sythesis in response to Ang II and potassium in salt-sensitive and salt-resistant hypertensive subjects. 2.) To determine the effect of genetic variation in CYP11B2 on vascular responsiveness to vasodilation before and after aldosterone receptor blockade. 3.) To determine whether genetic variation in CYP11B2 is associated with or linked to essential or salt-sensitive hypertension in African Americans and Caucasians. **This CRC Project submission will be focused on the completion of Specific Aim 1.
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