Immunoregulation by DHEA:To Prevent Cardiac Dysfunction

描述（由申请人提供）：本提案将研究CAM药物脱氢表雄酮硫酸酯（DHEAS）通过调节适应性免疫功能来改变心室功能的作用机制。将研究已建立的导致心室功能障碍的临床危险因素的啮齿动物模型，即：老年和代谢综合征。此外，衰老和代谢综合征是心衰（HF）的预测因素，独立于其他已知的危险因素，强调了CAM治疗方法的发展的必要性。目前，有26种批准的收缩期心衰治疗药物，但没有一种能逆转舒张期心衰的进展。我们的数据表明，免疫调节淋巴细胞功能对体内心脏结构和功能以及体外心脏成纤维细胞功能有直接影响。我们的数据支持衰老和代谢综合征都会导致免疫功能障碍和心室功能障碍的概念。关键目的是证明通过DHEAS的免疫调节特性，心室功能障碍可以通过免疫功能障碍的调节来预防或逆转。更具体地说，喂食高脂肪、高简单碳水化合物饮食产生代谢综合征的中年和年轻小鼠，心室功能显著扩张，辅助性T (TH)2淋巴细胞功能占优势。DHEAS促进TH1淋巴细胞功能，从而逆转由年龄和/或代谢综合征引起的TH2极化，从而阻止扩张性心室功能的进展或诱导消退。具体目的是通过体内和体外模型将淋巴细胞功能与心室基因、结构和功能联系起来，以证明DHEAS免疫调节对心脏结构和功能的影响。我们还将利用我们建立的CD4+淋巴细胞过继转移模型，转移到没有CD4+淋巴细胞的SCID小鼠身上。这将证明DHEAS修饰的CD4+淋巴细胞对心脏基因、结构和功能的直接影响。由于DHEAS调节TH1和TH2表型CD4+淋巴细胞，其对心脏结构和功能的免疫调节作用将被确定。从这些研究中获得的概念将为使用DHEAS作为CAM治疗来延缓发展和刺激与衰老和/或代谢综合征相关的扩张型心室功能障碍的消退提供基础。脱氢表雄酮（DHEA）是一种CAM药物，是肾上腺类固醇激素家族的一部分，在调节或“正常化”功能失调的免疫系统方面具有重要活性。最近，我们证明了CD4+淋巴细胞的失调深刻地改变了舒张功能和心脏细胞外基质（ECM）的组成。我们还表明，CD4+淋巴细胞分泌产物对体外原代心脏成纤维细胞功能有直接影响。我们的数据支持cd4 +淋巴细胞向TH2 （t -辅助性2）表型极化导致扩张型心肌病（DCM）的假设。我们最近的初步研究发现DHEAS（硫酸脱氢表雄酮）可以逆转由于衰老引起的左心室僵硬和纤维化，假设这种心脏重塑可以用DHEAS在衰老小鼠中已知的免疫调节活性的恢复来解释。本提案将研究CAM制剂DHEAS在通过淋巴细胞调节从而延缓心脏重塑和与年龄或饮食相关的功能障碍中改善心脏病的作用。

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.