Cardiovascular mortality during the past three to four years has plateaued. Among the proposed reasons accounting for this is our limited knowledge of the interaction of the mechanisms enhancing cardiovascular risk. This proposal is designed to address three of these: 1) the renin-angiotensin system (RAS), 2) the plasminogen- activator-inhibitor-1 (PAI-1) system, and 3) the metabolic abnormalities associated with insulin resistance. We have documented potential links in abnormalities in these systems, which are likely to be genetically- determined. Specifically, 1) the RAS profoundly influences vascular response, renal function, and PAI-1 production. 2) An abnormality in the RAS is uniquely associated with insulin resistance. 3) Substantial variations in the occurrence of vascular (pressor, renal and atherosclerotic) and metabolic complications in the hypertensive population may be secondary to variations in the functions of critical genes. Thus, our overall hypothesis is: In hypertension, it is insulin resistance, with differences in the specific alleles of the genes of the RAS and PAI-1 system, that predispose to vascular complications. To evalulate this hypothesis, we will: 1) determine the relationship between insulin sensitivity and the RAS gene profile; 2) test the hypothesis that variation in the pressor and renal hemodynamic responses to angiotensin II (AngII) is mediated by variations in the genetic environment, specifically, the angiotensinogen (AGT) and angiotensin converting enzyme (ACE) genes; 3) assess the relationships between PAI-1 levels, insulin resistance, and the activity of the RAS, and correlate these with PAI-1 and RAS genotypes; and 4) determine the functional significance of polymorphism in the PAI-1 and RAS genes. To accomplish these goals, patients with hypertension will undergo a phenotyping protocol in a controlled environment. Then, mechanistic studies will explore the relationship between the pressor, renal hemodynamic, and PAI-1 responsiveness and the genotypes and insulin resistance. We anticipate that these studies will clarify 1) the relationship between abnormalities in the RAS and insulin resistance, 2) the role of the RAS in mediating the vascular and atherosclerotic (directly and via its effect on the PAI-1 production) complications of human hypertension, and 3) the likelihood that the genetic environment can explain the variable expression of these complications. With this information, specific preventive and therapeutic measures to retard the development of these complications could be proposed and tested in a clinical trial's format.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059424-03
Application #
6183841
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Linder, Barbara
Project Start
1998-08-14
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
3
Fiscal Year
2000
Total Cost
$477,086
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Saxena, A R; Chamarthi, B; Williams, G H et al. (2014) Predictors of plasma and urinary catecholamine levels in normotensive and hypertensive men and women. J Hum Hypertens 28:292-7
Garg, Rajesh; Sun, Bei; Williams, Jonathan (2014) Effect of low salt diet on insulin resistance in salt-sensitive versus salt-resistant hypertension. Hypertension 64:1384-7
Vaidya, Anand; Underwood, Patricia C; Hopkins, Paul N et al. (2013) Abnormal aldosterone physiology and cardiometabolic risk factors. Hypertension 61:886-93
Rao, A D; Sun, B; Saxena, A et al. (2013) Polymorphisms in the serum- and glucocorticoid-inducible kinase 1 gene are associated with blood pressure and renin response to dietary salt intake. J Hum Hypertens 27:176-80
Chuengsamarn, Somlak; Garza, Amanda E; Krug, Alexander W et al. (2013) Direct renin inhibition modulates insulin resistance in caveolin-1-deficient mice. Metabolism 62:275-81
Sun, Bei; Chamarthi, Bindu; Williams, Jonathan S et al. (2012) Different polymorphisms of the mineralocorticoid receptor gene are associated with either glucocorticoid or mineralocorticoid levels in hypertension. J Clin Endocrinol Metab 97:E1825-9
Underwood, Patricia C; Chamarthi, Bindu; Williams, Jonathan S et al. (2012) Nonmodulation as the mechanism for salt sensitivity of blood pressure in individuals with hypertension and type 2 diabetes mellitus. J Clin Endocrinol Metab 97:3775-82
Carey, Robert M; Schoeffel, Cynthia D; Gildea, John J et al. (2012) Salt sensitivity of blood pressure is associated with polymorphisms in the sodium-bicarbonate cotransporter. Hypertension 60:1359-66
Williams, Jonathan S; Chamarthi, Bindu; Goodarzi, Mark O et al. (2012) Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension. Am J Hypertens 25:812-7
Underwood, Patricia C; Chamarthi, Bindu; Williams, Jonathan S et al. (2012) Replication and meta-analysis of the gene-environment interaction between body mass index and the interleukin-6 promoter polymorphism with higher insulin resistance. Metabolism 61:667-71

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