Heme oxygenase (HO)-1 converts heme to bilirubin, carbon monoxide, and iron. Our prior work has suggested a cardioprotective role for HO-1 in heart failure. To test whether HO-1 (heat shock protein 32) prevents cardiomyocyte apoptosis and cardiac dysfunction after ischemia-reperfusion (I/R), we generated transgenic mice overexpressing HO-1 in the heart under the control of the α-myosin heavy chain promoter. HO-1 transcript and protein increased markedly in the heart only. In an isolated heart preparation, we observed an enhanced functional recovery during reperfusion after ischemia in the transgenic hearts compared with nontransgenic controls. I/R injury was also performed in intact animals by coronary ligation and reperfusion to assess the protective role of HO-1 overexpression on heart apoptosis. HO-1 overexpression reduced cardiac apoptosis, as evidenced by fewer terminal deoxynucleodidyl transferase-mediated dUTP nick-end labeling-positive or in situ oligo ligation-positive myocytes, compared with nontransgenic mice. Our results indicate that cardioselective overexpression of HO-1 exerts a cardioprotective effect after myocardial I/R in mice, and this effect is probably mediated via an antiapoptotic action of HO-1.

Aims Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI. Methods and results To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1-/-) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1-/- and wild-type (WT) littermates. HSPB1 was up-regulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodelling and cardiac dysfunction in Hspb1-/- mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1-/- mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1-/- hearts exhibited enhanced and prolonged leucocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFκB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased nuclear factor-κB (NFκB) activation, which promoted the expression of proinflammatory mediators. This led to increased leucocyte recruitment, thereby to excessive inflammation, ultimately resulting in adverse remodelling, cardiac dysfunction, and cardiac rupture following MI. Conclusion These data suggest that HSPB1 acts as a negative regulator of NFκB-mediated leucocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18095号 / 理博第3973号 / 新制||理||1573(附属図書館) / 30953 / 京都大学大学院理学研究科化学専攻 / (主査)教授 三木 邦夫, 教授 杉山 弘, 教授 秋山 芳展 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18514号 / 医博第3934号 / 新制||医||1006(附属図書館) / 31400 / 京都大学大学院医学研究科医学専攻 / (主査)教授 上本 伸二, 教授 三森 経世, 教授 長田 重一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21339号 / 医博第4397号 / 新制||医||1031(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 井上 治久, 教授 宮本 享, 教授 林 康紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Several cDNAs isolated from brains of diapausing pupae of the flesh fly, Sarcophaga crassipalpis, show expression patterns unique to diapause. To isolate such cDNAs a diapause pupal brain cDNA library was screened by using an elimination hybridization technique, and cDNAs that did not hybridize with cDNA probes constructed from the RNA of nondiapausing pupae were selected for further screening. The 95 clones that did not hybridize in the initial library screen were selected for further characterization. These clones were then screened against diapause and nondiapause pupal poly(A)+ Northern blots. The secondary screen identified 4 diapause-up-regulated clones, 7 diapause-down-regulated clones, 8 clones expressed equally in both diapause and nondiapause, and 75 clones without detectable expression. The diapause- up-regulated and down-regulated clones were further characterized by partial DNA sequencing and identity searches by using GenBank. Identities between our cloned cDNAs and other genes included those linked to cell cycle progression, stress responses, and DNA repair processes. The results suggest that insect diapause is not merely a shutdown of gene expression but is a unique, developmental pathway characterized by the expression of a novel set of genes.

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