While several previous studies have indicated the link between periodontal disease (PD) and myocardial infarction (MI), theunderlying mechanisms remain unclear. Autophagy, a cellular quality control process that is ac...While several previous studies have indicated the link between periodontal disease (PD) and myocardial infarction (MI), theunderlying mechanisms remain unclear. Autophagy, a cellular quality control process that is activated in several diseases, includingheart failure, can be suppressed by Porphyromonas gingivalis (P.g.). However, it is uncertain whether autophagy impairment byperiodontal pathogens stimulates the development of cardiac dysfunction after MI. Thus, this study aimed to investigate therelationship between PD and the development of MI while focusing on the role of autophagy. Neonatal rat cardiomyocytes(NRCMs) and MI model mice were inoculated with wild-type P.g. or gingipain-deficient P.g. to assess the effect of autophagyinhibition by P.g. Wild-type P.g.-inoculated NRCMs had lower cell viability than those inoculated with gingipain-deficient P.g. Thisstudy also revealed that gingipains can cleave vesicle-associated membrane protein 8 (VAMP8), a protein involved in lysosomalsensitive factor attachment protein receptors (SNAREs), at the 47th lysine residue, thereby inhibiting autophagy. Wild-type P.g.-inoculated MI model mice were more susceptible to cardiac rupture, with lower survival rates and autophagy activity thangingipain-deficient P.g.-inoculated MI model mice. After inoculating genetically modified MI model mice (VAMP8-K47A) with wildtype P.g., they exhibited significantly increased autophagy activation compared with the MI model mice inoculated with wild-typeP.g., which suppressed cardiac rupture and enhanced overall survival rates. These findings suggest that gingipains, which arevirulence factors of P.g., impair the infarcted myocardium by cleaving VAMP8 and disrupting autophagy. This study confirms thestrong association between PD and MI and provides new insights into the potential role of autophagy in this relationship.展开更多
PGC-1α, a potent transcriptional coactivator, is the major regulator of mitochondrial biogenesis and activity in the cardiac muscle. The dysregulation of PGC-la and its target genes has been reported to be associated...PGC-1α, a potent transcriptional coactivator, is the major regulator of mitochondrial biogenesis and activity in the cardiac muscle. The dysregulation of PGC-la and its target genes has been reported to be associated with congenital and acquired heart diseases. By examining myocardium samples from patients with Tetralogy of Fallot, we show here that PGC-1α expression levels are markedly increased in patients compared with healthy controls and positively correlated with the severity of cyanosis. Furthermore, hypoxia significantly induced the expression of PGC-1α and mitochondrial biogenesis in cultured cardiac myocytes. Mechanistic studies suggest that hypoxia-induced PGC-1α expression is regulated through the AMPK signaling pathway. Together, our data indicate that hypoxia can stimulate the expression of PGC-1α and mitochondrial biogenesis in the cardiac myocytes, and this process might provide a potential adaptive mechanism for cardiac myocytes to increase ATP output and minimize hypoxic damage to the heart.展开更多
The aim of present study was to evaluate the feasibility and efficiency of enhanced green fluorescent protein （EGFP） gene delivery to myocardium in vivo by ultrasound targeted microbubble destruction （UTMD） and po...The aim of present study was to evaluate the feasibility and efficiency of enhanced green fluorescent protein （EGFP） gene delivery to myocardium in vivo by ultrasound targeted microbubble destruction （UTMD） and polyethylenimine （PEI）. SonoVue/DNA and PEI/DNA/SonoVue complexes were prepared. Gel electrophoresis analysis was performed to determine the structural integrity of plasmid DNA or PEI/DNA after UTMD. Solutions of plasmid DNA, SonoVue/DNA, PEI/DNA complexes or PEI/DNA/SonoVue complexes were respectively transduced into BALB/c mice hearts by means of transthoracic ultrasound irradiation. Mice undergoing PBS injection, plasmid injection or PEI/DNA complexes injection without ultrasound irradiation served as controls. Gene expression in myocardium was detected 4 days after treatment. Cryosections and histological examinations were conducted. Electrophoresis gel assay showed no damage to DNA or PEI/DNA complexes after UTMD. When the heart was not exposed to ultrasound, the expression of EGFP was observed in the subendocardial myocardium obviously. The strongest expression was detected in the anterior wall of the left ventricle when the heart was exposed to ultrasound alone. Injection of PEI/DNA complexes and UTMD resulted in the highest transfection efficiency and the distributional difference of EGFP was not obvious. No tissue damage was seen histologically. In conclusion, a combination of UTMD and PEI was highly effective in transfecting mice hearts without causing any apparently adverse effect. It provides an alternative to current clinical gene therapy and opens a new concept of non-viral gene delivery for the treatment of cardiac disease.展开更多
基金supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research (C) 20K08399 (to Yasuhiro Maejima)KAKENHI 19K18985,Grant-in-Aid for JSPS Fellows+1 种基金MSD Life Science FoundationPublic Interest Incorporated Foundation (to Yuka Shiheido-Watanabe)
文摘While several previous studies have indicated the link between periodontal disease (PD) and myocardial infarction (MI), theunderlying mechanisms remain unclear. Autophagy, a cellular quality control process that is activated in several diseases, includingheart failure, can be suppressed by Porphyromonas gingivalis (P.g.). However, it is uncertain whether autophagy impairment byperiodontal pathogens stimulates the development of cardiac dysfunction after MI. Thus, this study aimed to investigate therelationship between PD and the development of MI while focusing on the role of autophagy. Neonatal rat cardiomyocytes(NRCMs) and MI model mice were inoculated with wild-type P.g. or gingipain-deficient P.g. to assess the effect of autophagyinhibition by P.g. Wild-type P.g.-inoculated NRCMs had lower cell viability than those inoculated with gingipain-deficient P.g. Thisstudy also revealed that gingipains can cleave vesicle-associated membrane protein 8 (VAMP8), a protein involved in lysosomalsensitive factor attachment protein receptors (SNAREs), at the 47th lysine residue, thereby inhibiting autophagy. Wild-type P.g.-inoculated MI model mice were more susceptible to cardiac rupture, with lower survival rates and autophagy activity thangingipain-deficient P.g.-inoculated MI model mice. After inoculating genetically modified MI model mice (VAMP8-K47A) with wildtype P.g., they exhibited significantly increased autophagy activation compared with the MI model mice inoculated with wild-typeP.g., which suppressed cardiac rupture and enhanced overall survival rates. These findings suggest that gingipains, which arevirulence factors of P.g., impair the infarcted myocardium by cleaving VAMP8 and disrupting autophagy. This study confirms thestrong association between PD and MI and provides new insights into the potential role of autophagy in this relationship.
基金Supplementary information is linked to the online version of the paper on the Cell Research website. Acknowledgments We thank Yun Luo, Jia Jia and Dr Yun Xu at Nanjing University, Nanjing, China, for their scientific discussions and experimental assistance. This work was supported by grants from the National Natural Science Foundation of China （Nos. 30871195, 90813035, 30890044）, the National Basic Research Program of China （Nos. 2006CB503909, 2004CB518603）, the ＂111＂ Project, the Hi-Tech Research and Development Program of China （No. 2006AA02A112,）, and the Natural Science Foundation of Jiangsu Province （Nos. BK2004082, BK2006714, BK2008021）.
文摘PGC-1α, a potent transcriptional coactivator, is the major regulator of mitochondrial biogenesis and activity in the cardiac muscle. The dysregulation of PGC-la and its target genes has been reported to be associated with congenital and acquired heart diseases. By examining myocardium samples from patients with Tetralogy of Fallot, we show here that PGC-1α expression levels are markedly increased in patients compared with healthy controls and positively correlated with the severity of cyanosis. Furthermore, hypoxia significantly induced the expression of PGC-1α and mitochondrial biogenesis in cultured cardiac myocytes. Mechanistic studies suggest that hypoxia-induced PGC-1α expression is regulated through the AMPK signaling pathway. Together, our data indicate that hypoxia can stimulate the expression of PGC-1α and mitochondrial biogenesis in the cardiac myocytes, and this process might provide a potential adaptive mechanism for cardiac myocytes to increase ATP output and minimize hypoxic damage to the heart.
基金a grant from the National Natural Sciences Foundation of China (No. 30670548).
文摘The aim of present study was to evaluate the feasibility and efficiency of enhanced green fluorescent protein （EGFP） gene delivery to myocardium in vivo by ultrasound targeted microbubble destruction （UTMD） and polyethylenimine （PEI）. SonoVue/DNA and PEI/DNA/SonoVue complexes were prepared. Gel electrophoresis analysis was performed to determine the structural integrity of plasmid DNA or PEI/DNA after UTMD. Solutions of plasmid DNA, SonoVue/DNA, PEI/DNA complexes or PEI/DNA/SonoVue complexes were respectively transduced into BALB/c mice hearts by means of transthoracic ultrasound irradiation. Mice undergoing PBS injection, plasmid injection or PEI/DNA complexes injection without ultrasound irradiation served as controls. Gene expression in myocardium was detected 4 days after treatment. Cryosections and histological examinations were conducted. Electrophoresis gel assay showed no damage to DNA or PEI/DNA complexes after UTMD. When the heart was not exposed to ultrasound, the expression of EGFP was observed in the subendocardial myocardium obviously. The strongest expression was detected in the anterior wall of the left ventricle when the heart was exposed to ultrasound alone. Injection of PEI/DNA complexes and UTMD resulted in the highest transfection efficiency and the distributional difference of EGFP was not obvious. No tissue damage was seen histologically. In conclusion, a combination of UTMD and PEI was highly effective in transfecting mice hearts without causing any apparently adverse effect. It provides an alternative to current clinical gene therapy and opens a new concept of non-viral gene delivery for the treatment of cardiac disease.
