Elevated levels of aldosterone are associated with impaired endothelium-dependent vasodilation in patients with hypertension and congestive heart failure. Although poorly understood, several mechanisms have been implicated to explain the adverse effects of aldosterone on endothelial cell (EEC) function including decreased nitric oxide (NO.) production and/or increased oxidant stress (OS). The applicant has previously demonstrated that glucose-6- phosphate dehydrogenase (G6PD), the first enzyme in the pentose phosphate pathway and principal intracellular source of NADPH, modulates EC function by regulating nitric oxide (NO.) production and limiting vascular OS. Aldosterone-mediated inhibition of G6PD represents a unifying mechanism by which aldosterone may impair EC function and vasodilation. Aldosterone is known to influence gene transcription and inhibition of G6PD, in turn, will result in decreased NO. levels and increased vascular OS to promote EC dysfunction. With the Independent Scientist Award (K02), the applicant will use the time protected by this award examine the molecular mechanisms by which aldosterone modulates G6PD to impair EC function. The applicant will place an intensive research focus on studies that will examine the effect of aldosterone on G6PD expression and the resulting functional consequences in EC in vitro. The in vivo significance of these findings will be confirmed using novel vascular gene transfer techniques and transgenic murine models. The applicant is a principal investigator in the Whitaker Cardiovascular Institute at Boston University School of Medicine, which provides a rich intellectual environment to establish the groundwork for this line of investigation. As evidenced by seven years of vascular biology research, the applicant remains firmly committed to a long-term career in basic science investigation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02HL081110-03
Application #
7283640
Study Section
Special Emphasis Panel (ZHL1-CSR-B (M2))
Program Officer
Commarato, Michael
Project Start
2005-09-15
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$100,359
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhang, Zhaoyun; Yang, Zhihong; Zhu, Bo et al. (2012) Increasing glucose 6-phosphate dehydrogenase activity restores redox balance in vascular endothelial cells exposed to high glucose. PLoS One 7:e49128
Michas, George; Liberman, Marcel; Becker, Kristian C et al. (2011) Reciprocal regulation of 11ýý-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor expression by dexamethasone inhibits human coronary artery smooth muscle cell proliferation in vitro. Mol Cell Biochem 346:69-79
Xu, Yizhen; Zhang, Zhaoyun; Hu, Ji et al. (2010) Glucose-6-phosphate dehydrogenase-deficient mice have increased renal oxidative stress and increased albuminuria. FASEB J 24:609-16
Hadri, Lahouaria; Bobe, Regis; Kawase, Yoshiaki et al. (2010) SERCA2a gene transfer enhances eNOS expression and activity in endothelial cells. Mol Ther 18:1284-92
Maron, Bradley A; Leopold, Jane A (2010) Aldosterone receptor antagonists: effective but often forgotten. Circulation 121:934-9
Leopold, Jane A (2010) Redox Pioneer: Professor Joseph Loscalzo. Antioxid Redox Signal 13:1125-32
Leopold, Jane A; Loscalzo, Joseph (2009) Oxidative risk for atherothrombotic cardiovascular disease. Free Radic Biol Med 47:1673-706
Maron, Bradley A; Zhang, Ying-Yi; Handy, Diane E et al. (2009) Aldosterone increases oxidant stress to impair guanylyl cyclase activity by cysteinyl thiol oxidation in vascular smooth muscle cells. J Biol Chem 284:7665-72
Leopold, Jane A (2009) Rapid aldosterone signaling and vascular reactivity: relax or don't do it. J Cardiovasc Pharmacol 54:465-7
Leopold, Jane A; Loscalzo, Joseph (2008) Oxidative mechanisms and atherothrombotic cardiovascular disease. Drug Discov Today Ther Strateg 5:5-13

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