Effects of Salacia oblonga root extract on cardiac hypertrophy

长圆五层龙根提取物对心脏肥大的影响

基本信息

批准号：
7637625
负责人：
QINGLIN YANG
金额：
$ 13.18万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7637625
关键词：
Angiotensin II Antioxidants Atrial Natriuretic Factor Attenuated Ayurvedic Medicine Cardiac Cardiac Myocytes Cardiomyopathies Carnitine Celastraceae Chinese People Chinese Traditional Medicine Condition Congestive Heart Failure Constriction procedure Data Development Diabetes Mellitus Dose Enzymes Fatty Acids Fatty acid glycerol esters Fibrosis Gene Expression Gene Targeting Generations Genetic Genetic Transcription Growth Hand Heart Heart Diseases Heart Hypertrophy Heart failure Homeostasis Hyperglycemia Hypertension Hypertrophy In Vitro Knock-out Knockout Mice Left Lipids Medicine Metabolic Metabolic Diseases Methods Mitochondria Molecular Morphology Mus Muscle Cells Mutation Myocardial Nuclear Receptors Numbers Obesity Oxidation-Reduction Oxidative Stress PPAR alpha PPAR delta Peroxisome Proliferator-Activated Receptors Personal Satisfaction Phenylephrine Physiologic intraventricular pressure Physiological Plant Roots Play Population Protein Biosynthesis Rattus Reactive Oxygen Species Risk Factors Role Staging Stimulus Stress Structure Superoxides Testing Traditional Medicine Transcriptional Activation Transcriptional Regulation Transferase Ventricular Remodeling Water diabetic fatty acid oxidation improved in vivo lipid metabolism macrophage mangiferin member mouse model novel novel therapeutics peroxisome pressure prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：心脏肥大是充血性心力衰竭的主要危险因素，充血性心力衰竭是许多心脏疾病的终末期病症。心脏中脂质和氧化还原稳态的失调与心脏肥大和心力衰竭的发展有关。长五层龙根的水提取物是一种广泛用于治疗糖尿病和肥胖的阿育吠陀药物和中药，已被证明可以改善 Zucker 糖尿病脂肪大鼠的餐后高血糖和心脏纤维化。长圆五层龙根提取物 (SORE) 已被证明可以激活过氧化物酶体增殖物激活受体 α (PPARα)，它是核受体超家族的成员。我们的初步研究表明，Zucker 瘦大鼠的 SORE 治疗激活了肉碱棕榈酰转移酶 I 的心脏表达，肉碱棕榈酰转移酶 I 是线粒体脂肪酸氧化 (FAO) 的关键酶。此外，SORE 还能抑制血管紧张素 II 和去氧肾上腺素诱导的培养心肌细胞的肥大生长。我们将使用体外、体内和离体方法相结合来检验我们的中心假设，即 SORE 通过激活 PPARα 来纠正伴随的心肌 FAO 减少以及由于心肌细胞缺乏 PPARδ（控制 FAO 的另一种 PPAR 亚型）来改善病理性心脏肥大。我们还将测试 SORE 充当抗氧化剂以防止心脏氧化损伤的假设。具体来说，我们将实现以下具体目标：1、明确SORE治疗对小鼠压力超负荷引起的心脏肥大发展的影响； 2、确定SORE抗肥厚作用的机制是否与其PPARα激活作用相关； 3、确定SORE是否作为抗氧化剂发挥其抗肥厚作用。我们将描述 SORE 对压力超负荷条件下 PPARα 缺失小鼠和心肌细胞限制性 PPARδ 敲除小鼠的基因表达、心脏形态、心脏功能和氧化应激的影响。这些研究的结果应该提供新的药理学机制，说明 SORE 对心脏代谢紊乱的潜在调节作用，这些紊乱与心脏肥大有关，以响应肥大刺激或关键脂肪酸代谢转录调节因子的遗传缺陷。这项研究的结果应该为预防和治疗心脏肥大和心力衰竭提供新的治疗选择。心脏肥大是充血性心力衰竭的主要危险因素，充血性心力衰竭是许多心脏疾病的终末期病症。拟议的研究将为 SORE 对与心脏肥大相关的心脏代谢紊乱的潜在调节作用提供新的药理学机制。这项研究的结果应该为预防和治疗心脏肥大和心力衰竭提供新的治疗选择。