Immunoregulation by DHEA:To Prevent Cardiac Dysfunction

DESCRIPTION (provided by applicant): This proposal will examine the mechanism of action of the CAM agent, dehydroepiandrosterone-sulfate (DHEAS) on modification of cardiac ventricular function via regulation of the adaptive immune function. Established rodent models of clinical risk factors that result in cardiac ventricular dysfunction will be studied, namely: advancing middle age and metabolic syndrome. Moreover, aging and metabolic syndrome are predictors of heart failure (HF) independent of other established risk factors, underscoring the need for the development of CAM therapeutics. Currently, there are 26 approved therapeutics for systolic HF- none of which reverse the progression of the diastolic HF. Our data suggest that immune modulation of lymphocyte function has direct effects on the cardiac structure and function in vivo and cardiac fibroblast functions in vitro. Our data support the concept that both aging and metabolic syndrome induce immune dysfunction and ventricular dysfunction. The key objective is to demonstrate that through the immunomodulatory properties of DHEAS ventricular dysfunction will be prevented or reversed by regulation of immune dysfunction. More specifically middle aged as well as young mice fed a high-fat high-simple carbohydrate diet producing a metabolic syndrome have significantly dilated ventricular function with a dominance of T helper (TH)2 lymphocyte function. DHEAS promotes TH1 lymphocyte function which should reverse TH2 polarization induced by age and/or metabolic syndrome, thereby halting the progression or inducing regression of the dilated ventricular function. The specific aims will associate lymphocyte function with ventricular gene, structure and function using in vivo and in vitro models to demonstrate the effects of immune regulation by DHEAS on cardiac structure and function. We will also exploit our established model of CD4+ lymphocyte adoptive transfer to naive SCID mice which are without CD4+ lymphocytes. This will demonstrate a direct effect of DHEAS modified CD4+ lymphocytes on cardiac gene, structure, and function. As DHEAS regulates the TH1 and TH2 phenotype CD4+ lymphocytes its immunoregulatory actions on cardiac structure and functions will be defined. The concepts gained from these studies will provide a basis for use of DHEAS as a CAM therapeutic to retard development and stimulate regression of dilated ventricular dysfunction associated with aging and/or metabolic syndrome. Dehydroepiandrosterone (DHEA), a CAM agent, is part of a family of adrenal steroid hormones with significant activity in regulating or "normalizing" dysfunctional immune systems. Recently we demonstrated that dysregulation of CD4+ lymphocytes profoundly and adversely altered diastolic function and cardiac extracellular matrix (ECM) composition. We have also shown that CD4+lymphocyte secretory products have a direct effect on primary cardiac fibroblast function in vitro. Our data support the hypothesis that polarization ofCD4+ lymphocytes to TH2 (T-helper 2) phenotype results in dilated cardiomyopathy (DCM). Our recent preliminary study found that DHEAS (DHEA-sulfate) reversed left ventricular stiffness and fibrosis due to aging, hypothesizing that such cardiac remodeling can be explained by DHEAS' known restoration of immunoregulatory activity in the aged mouse. This proposal will examine the role of the CAM agent, DHEAS in ameliorating heart disease through lymphocyte regulation thereby retarding cardiac remodeling and dysfunction associated with age or diet.

DESCRIPTION (provided by applicant): This proposal will examine the mechanism of action of the CAM agent, dehydroepiandrosterone-sulfate (DHEAS) on modification of cardiac ventricular function via regulation of the adaptive immune function. Established rodent models of clinical risk factors that result in cardiac ventricular dysfunction will be studied, namely: advancing middle age and metabolic syndrome. Moreover, aging and metabolic syndrome are predictors of heart failure (HF) independent of other established risk factors, underscoring the need for the development of CAM therapeutics. Currently, there are 26 approved therapeutics for systolic HF- none of which reverse the progression of the diastolic HF. Our data suggest that immune modulation of lymphocyte function has direct effects on the cardiac structure and function in vivo and cardiac fibroblast functions in vitro. Our data support the concept that both aging and metabolic syndrome induce immune dysfunction and ventricular dysfunction. The key objective is to demonstrate that through the immunomodulatory properties of DHEAS ventricular dysfunction will be prevented or reversed by regulation of immune dysfunction. More specifically middle aged as well as young mice fed a high-fat high-simple carbohydrate diet producing a metabolic syndrome have significantly dilated ventricular function with a dominance of T helper (TH)2 lymphocyte function. DHEAS promotes TH1 lymphocyte function which should reverse TH2 polarization induced by age and/or metabolic syndrome, thereby halting the progression or inducing regression of the dilated ventricular function. The specific aims will associate lymphocyte function with ventricular gene, structure and function using in vivo and in vitro models to demonstrate the effects of immune regulation by DHEAS on cardiac structure and function. We will also exploit our established model of CD4+ lymphocyte adoptive transfer to naive SCID mice which are without CD4+ lymphocytes. This will demonstrate a direct effect of DHEAS modified CD4+ lymphocytes on cardiac gene, structure, and function. As DHEAS regulates the TH1 and TH2 phenotype CD4+ lymphocytes its immunoregulatory actions on cardiac structure and functions will be defined. The concepts gained from these studies will provide a basis for use of DHEAS as a CAM therapeutic to retard development and stimulate regression of dilated ventricular dysfunction associated with aging and/or metabolic syndrome. Dehydroepiandrosterone (DHEA), a CAM agent, is part of a family of adrenal steroid hormones with significant activity in regulating or "normalizing" dysfunctional immune systems. Recently we demonstrated that dysregulation of CD4+ lymphocytes profoundly and adversely altered diastolic function and cardiac extracellular matrix (ECM) composition. We have also shown that CD4+lymphocyte secretory products have a direct effect on primary cardiac fibroblast function in vitro. Our data support the hypothesis that polarization ofCD4+ lymphocytes to TH2 (T-helper 2) phenotype results in dilated cardiomyopathy (DCM). Our recent preliminary study found that DHEAS (DHEA-sulfate) reversed left ventricular stiffness and fibrosis due to aging, hypothesizing that such cardiac remodeling can be explained by DHEAS' known restoration of immunoregulatory activity in the aged mouse. This proposal will examine the role of the CAM agent, DHEAS in ameliorating heart disease through lymphocyte regulation thereby retarding cardiac remodeling and dysfunction associated with age or diet.