Aldosterone is implicated in the process of myocardial remodeling and failure . Aldosterone may affect myocardial phenotype by regulating inflammation, myocyte contraction and relaxation, oxidative stress, and the interstitial matrix through a variety of mechanisms. In in vitro studies, aldosterone induces myocyte apoptosis, p67 phox and pro-inflammatory signal mediators such as NOS2. These observations lead us to the hypothesis that aldosterone mediates the phenotypic responses of myocardial cells in hemodynamic overload and increased aldosterone system stimulation . Peroxisome proliferator-activated receptor (PPAR) signaling , although regulators of energy control, attenuate cardiac hypertrophy, oxidative stress and apoptosis and may improve myocardial remodeling through pathways such as inflammation . We will explore these pathways by manipulating aldosterone levels, in vivo in mice and in vitro in cardiac myocytes and fibroblasts and their interaction with PPARs in mediating structural and functional remodeling at the molecular, cellular and organ levels.
In Aim 1 we will test the role of aldosterone and PPARs in mediating pressure overload cardiac remodeling . We will test the hypothesis that PPARs inhibit aldosterone-induced adverse cardiac remodeling. We will use mice with pressure overload and chroni c aldosterone infusions . We will use synthetic PPAR activators, fenofibrate and troglitazone, to determine if cardiac remodeling is inhibite d and further test if aldosterone mediates remodeling via progression of chronic inflammation or oxidative stress in the myocardium of PPARalpha null mice.
In Aim 2 we will test the role of aldosterone in inducing a hypertrophic/proliferative and apoptotic phenotype in myocardial remodeling . In in vivo experiments, we will test the mechanism whereby aldosterone induces a myocardial phenotype via a) the EGFR and MAPK pathway;and b) oxidative stress.
In Aim 3 we will test the role of aldosterone in mediating an abnormal myocyte contractile phenotype. We will test the hypothesis that aldosterone exerts both acute and chronic effects on myocyte contractile phenotype. Myocyte contraction/relaxation and intracellular calcium transients will be measured simultaneously in adult rat and mouse myocytes following short (min ) or long (hrs) term exposure to exogenous aldosterone in vitro. These studies will provide new understanding of the mechanisms of aldosterone signaling in the pressure overload heart and will have direct relevance to a common cause of heart failure in patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Garcia, Anthony G; Wilson, Richard M; Heo, Joline et al. (2012) Interferon-? ablation exacerbates myocardial hypertrophy in diastolic heart failure. Am J Physiol Heart Circ Physiol 303:H587-96
Greene, Michael J; Sam, Flora; Soo Hoo, Pamela T et al. (2011) Evidence for a functional role of the molecular chaperone clusterin in amyloidotic cardiomyopathy. Am J Pathol 178:61-8
Essick, Eric E; Sam, Flora (2011) Cardiac hypertrophy and fibrosis in the metabolic syndrome: a role for aldosterone and the mineralocorticoid receptor. Int J Hypertens 2011:346985
Essick, Eric E; Ouchi, Noriyuki; Wilson, Richard M et al. (2011) Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301:H984-93
Seldin, David C; Berk, John L; Sam, Flora et al. (2011) Amyloidotic cardiomyopathy: multidisciplinary approach to diagnosis and treatment. Heart Fail Clin 7:385-93
Biolo, Andreia; Shibata, Rei; Ouchi, Noriyuki et al. (2010) Determinants of adiponectin levels in patients with chronic systolic heart failure. Am J Cardiol 105:1147-52
Sam, Flora; Duhaney, Toni-Ann S; Sato, Kaori et al. (2010) Adiponectin deficiency, diastolic dysfunction, and diastolic heart failure. Endocrinology 151:322-31
Quiroz, Rene; Joseph, Lija; Sam, Flora (2010) Serial troponin-I measurement as a diagnostic and therapeutic tool in chronic myocarditis. J Heart Lung Transplant 29:820-2
De Silva, Deepa S; Wilson, Richard M; Hutchinson, Christoph et al. (2009) Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms. Am J Physiol Heart Circ Physiol 296:H1983-93
Ikeda, Yasumasa; Sato, Kaori; Pimentel, David R et al. (2009) Cardiac-specific deletion of LKB1 leads to hypertrophy and dysfunction. J Biol Chem 284:35839-49

Showing the most recent 10 out of 18 publications