| Summary: | 碩士 === 中山醫學大學 === 生化暨生物科技研究所 === 93 === PartI: The obese Zucker rat, a genetic model of morbid obesity, presents many of the same cardiopulmonary deficits as noted in obese humans. Severe obesity in human has long been recognized as causing a form of cardiomyopathy characterized by increased rates of hypertension, chronic volume overload, left ventricular hypertrophy and the development of heart failure. However, the precise mechanisms of cardiac apoptosis and hypertrophy in sever obesity remain uncertain. The purpose of this study was to evaluate the key components of apoptotic and hypertrophic pathways in excised heart from obesity.
Twelve obese Zucker rats were studied at 4~5 months of age and twelve age-matched lean Zucker rats served as control. The myocardial architecture and key components of mitochondrial-dependent apoptotic pathway, Fas recetopr-dependent apoptotic pathway, IL-6-MEK5-ERK-5 hypertrophic pathway in the excised left ventricle from rats were measured by histological analysis, Western blotting and reverse transcription polymerase chain reaction (RT-PCR).In the mitochondria dependent apoptotic pathway, we detect the pro-apoptotic protein（BNIP3、Bad）increased and anti-apoptotic protein (Bcl2) decreased. Besides, Cytochrome c released to the cytoplasm from mitochondria highly then Caspase 9 and Caspase 3 would be activated to make cardiac muscle apoptosis. In the Fas-death receptor dependent pathway,we detect Fas、FADD、acitvated-Caspase 8 and acitvated-Caspase 3 increased to make obese Zucker rats cardiac muscle apoptosis. In IL-6-MEK5-ERK-5 hypertrophic pathway, we found that dilated cardiomyopathy is may be mediated through IL-6 and MEK5-ERK5 pathway activation identified by Western blotting experiment.The cardiac apoptotic and hypertrophic pathways were more active in obese Zucker rat, which may provide one of possible apoptotic and hypertrophic mechanism for developing heart failure in obesity.
Part II:The obese Zucker rat, a genetic model of morbid obesity, presents many of the same cardiopulmonary deficits as noted in obese humans. Nocturnal hypoxemia during sleeping hours or intermittent hypoxia implicated in the pathogenesis of cardiac complications were often reported in severe obesity. The main purpose of this study was to explore the cardiac hypertrophy and apoptosis in obese Zucker Rat under long-term intermittent hypoxia.
Twelve obese Zucker rats and twelve age-matched lean Zucker rats were divided into four groups including normoxia in lean group, normoxia in obese group，hypoxia in lean group, and hypoxia in obese group. The hypoxia group were housed in a hypoxic chamber (12% O2, 88% N2 ), 8 hour per day for 7 days. The myocardial architecture and key components of mitochondrial-dependent apoptotic pathway, Fas recetopr-dependent apoptotic pathway, IL-6-MEK5-ERK-5 hypertrophic pathway in the excised left ventricle from rats were measured by histological analysis, Western blotting and reverse transcription polymerase chain reaction (RT-PCR).
The activity levels of IL-6-MEK5-ERK5 hypertrophic pathway, death-receptor pathway (Fas、FADD、Bid、activated-Caspase 8 and activated-Caspase 3) and mitochondrial dependent apoptotic pathway (BNIP3, Bad and cytosolic cytochrome c, activated caspase 9) were increased in lean rat heart after long-term intermittent hypoxia. The activity levels of IL-6-MEK5-ERK5 hypertrophic pathway, death-receptor pathway and mitochondrial dependent apoptotic pathway were increased in obese rat hearts, compared with lean rat heart and further increased after long-term intermittent hypoxia in obese rat hearts, compared with either lean in hypoxia group or obese in normoxia group. Long term intermittent hypoxia and obesity itself would make additively deleterious effects on cardiac tissues in obese Zucker Rat. Our findings imply that intermittent hypoxia and obesity itself will additively increases cardiac hypertrophy through IL6-MEK5-ERK5 pathway and additively increases cardiac apoptosis in obese rat heart through mitochondrial dependent apoptotic pathway and death receptor dependent pathway.
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