京都大学 / 新制・論文博士 / 博士(医学) / 乙第13449号 / 論医博第2242号 / 新制||医||1054(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 妹尾 浩, 教授 柳田 素子 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Cardioplegic arrest during heart operations is often used in cardiac surgery. During cardioplegia, the heart is subjected to a global ischemia/reperfusion-injury. ()-epigallocatechin gallate (EGCG), one of the main ingredients of green tea, seems to be beneficial in various cardiac diseases. Therefore, the aim of our study was to evaluate EGCG in a rabbit model of cardioplegic arrest. Twenty four mature Chinchilla rabbits were examined. Rabbit hearts were isolated and perfused according to Langendorff. After induction of cardioplegia (without and with 20 mol/L EGCG, n = 6 each) the hearts maintained arrested for 90-min. Thereafter, the hearts were re-perfused for 60 min. During the entire experiment hemodynamic and functional data were assessed. At the end of each experiment, left ventricular samples were processed for ATP measurements and for histological analysis. Directly after cessation of cardioplegia, all hearts showed the same decline in systolic and diastolic function. However, hearts of the EGCG-group showed a significantly faster and better hemodynamic recovery during reperfusion. In addition, tissue ATP-levels were significantly higher in the EGCG-treated hearts. Histological analysis revealed that markers of nitrosative and oxidative stress were significantly lower in the EGCG group. Thus, addition of EGCG significantly protected the cardiac muscle from ischemia/reperfusion injury.

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第25500号 / 医博第5100号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 齊藤 博英, 教授 松田 秀一, 教授 岩田 想 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Insulin resistance and chronic hyperglycemia promote vascular damage, increase circulating levels of inflammatory cytokines and lead to increased morbidity and mortality. MicroRNAs (miRs) -103/107 have been shown to negatively regulate insulin sensitivity and glucose homeostasis. Based on complimentary binding profiles, the downstream target gene of miR-103/107 is caveolin-1 (Cav-1). We hypothesized that daily administration of the phosphodiesterase-5 inhibitor tadalafil (TAD) ± the curcumin analogue (HO-3867) will attenuate inflammation, improve metabolic parameters and reduce infarct size after ischemia/reperfusion injury (IRI). Furthermore, we propose that TAD therapy will reduce myocardial expression of miR-103/107 and increase mRNA and protein levels of its target gene, Cav-1. Leptin receptor null mice were randomized to receive daily injections of TAD (1mg/kg), HO-3867 (25mg/Kg), combination therapy, or control for 12weeks with weight and fasting glucose monitored weekly. Upon completion, cardiomyocytes were isolated from each group and were subjected to simulated ischemia and reoxygenation (SI/RO) for cell viability and reactive oxygen species (ROS) measurement. Another set were subjected to IRI in a Langendorff model. Plasma samples were taken to measure plasma concentrations of cytokines. For miR expression, total RNA was isolated from TAD and DMSO treated mice and was subjected to reverse transcription and real time PCR using miR assay probes to determine expression. TAD, HO-3867 and the combination of both attenuated fasting glucose levels, reduced myocardial infarct size after IRI and inflammatory cytokines when compared to control (p<0.05 for each vs. control). Cardiomyocytes isolated from each treatment groups and subjected to SI/RO demonstrated reduced necrosis as shown by trypan blue exclusion assay, ROS generation, and improved mitochondrial membrane potential as compared to DMSO (control). Likewise, both mRNA and protein expression of Cav-1 were reduced in diabetic hearts but were significantly increased in TAD treated diabetic mice, which may be a mechanism to improve insulin signaling through downregulation of miR-103/107 and upregulation of Cav-1. These studies suggest that TAD alone or in combination may be a unique strategy to improve metabolic parameters and precondition diabetic hearts against IRI.

IN ENGLISH The ischemia-reperfusion (I/R) injury, which is a consequence of myocardial infarction, represents a major cause of death worldwide. One of the most effective cardioprotective interventions increasing the resistance of hearts to the I/R injury is the adaptation to a chronic hypoxia (CH). However, the molecular mechanisms of CH are still not well understood. The most important factors responsible for the I/R injury are reactive oxygen species (ROS) produced by complexes I and III within the mitochondrial electron transport chain. Potential candidates maintaining ROS at a low level are mitochondrial creatine kinase (mtCK) and two hexokinase isoforms (HK1 and HK2). These enzymes highly support the mitochondrial oxidative phosphorylation by increasing the availability of ADP for complex V of the respiratory chain. In addition, the HK binding to mitochondria inhibits binding of the pro- apoptotic protein BAX, thereby protecting cardiac cells against apoptosis. Besides the mitochondrial CK isoform, there are two cytosolic CK (CKM and CKB) present in cardiomyocytes that help to maintain energy homeostasis. Based on the known anatomical and physiological differences between the left (LV) and the right (RV) ventricles, the first study focused on the comparing ventricles in terms of the energy...