Cardiac hypertrophy is the main risk factor for congestive heart failure, which is the end-stage condition of a number of cardiac disorders. Deregulations of lipid and redox homeostasis in the heart are involved in the development of cardiac hypertrophy and heart failure. Water extract of Salacia oblonga root, a broadly used Ayuvedic medicine and traditional Chinese medicine for diabetes and obesity has been shown to improve postprandial hyperglycemia and cardiac fibrosis in Zucker Diabetic Fat rats. Salacia oblonga root extract (SORE) has been shown to activate Peroxisome proliferater activated receptor alpha (PPARalpha), a member of the nuclear receptor superfamily. Our preliminary studies revealed that SORE treatment in Zucker lean rats activated cardiac expression of carnitine palmitoyl transferase I, a key enzyme in mitochondria fatty acid oxidation (FAO). Furthermore, SORE suppressed Angiotensin II and phenylepherine induced hypertrophic growth in cultured cardiomyocytes. We will use a combination of in vitro, in vivo and ex vivo methods to test our central hypothesis that SORE improves pathological cardiac hypertrophy by activating PPARalpha to correct the companied diminished myocardial FAO and due to cardiomyocyte deficiency of PPARdelta, another PPAR subtype that govern FAO. We will also test a hypothesis that SORE acts as antioxidants to prevent oxidative damage to the heart. Specifically, we will achieve the following specific aims:1, define the effects of SORE treatment on the development of cardiac hypertrophy in response to pressure-overload in mice; 2, identify whether the mechanism underlying SORE's antihypertrophic effect is correlated with its PPARalpha activation action; 3, determine if SORE acts as anti-oxidant to exert its anti-hypertrophic effects. We will characterize effects of SORE on gene expression, cardiac morphology, cardiac function and oxidative stress in mice with PPARalpha null under pressure-overload condition and in mice with cardiomyocyte-restricted PPARdelta knockout. Results from these studies should provide novel pharmacological mechanisms on the potential regulating effects of SORE on cardiac metabolic disorders that are associated with cardiac hypertrophy in response to hypertrophic stimuli or genetic defect of a key fatty acid metabolic transcriptional regulator. Results from this study should provide novel therapeutic option in preventing and treating cardiac hypertrophy and heart failure. Cardiac hypertrophy is the main risk factor for congestive heart failure, which is the end-stage condition of a number of cardiac disorders. The proposed study will provide novel pharmacological mechanisms on the potential regulating effects of SORE on cardiac metabolic disorders that are associated with cardiac hypertrophy. Results from this study should provide novel therapeutic option in preventing and treating cardiac hypertrophy and heart failure. ? ? ?
