Cardiovascular-Specific PSEN1 Deletion Leads to Abnormalities in Calcium homeostasis
Cardiovascular-Specific PSEN1 Deletion Leads to Abnormalities in Calcium homeostasis
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DOI：
10.1002/cbin.11753
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发表时间：
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影响因子：
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通讯作者：
胡淑婷
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作者：
宋晓伟;赵峰;杨静;袁青宁;曾振宇;沈明;汤莹;曹密;沈亚峰;李松华;杨勇骥;吴弘;赵仙先;胡淑婷
Mutations of PSEN1 have been reported in dilated cardiomyopathy pedigrees. Understanding the effects and mechanisms of PSEN1 in cardiomyocytes might have .important implications for treatment of heart diseases. Here, we showed that PSEN1.was down-regulated in ischemia-induced failing hearts. Functionally, cardiovascular .specific PSEN1 deletion led to spontaneous death of the mice due to cardiomyopathy..At the age of 11 months, the ratio of the heart weight/body weight was slightly lower .in the Sm22a-PSEN1-KO mice compared with that of the WT mice..Echocardiography showed that the percentage of ejection fraction and fractional .shortening was significantly reduced in the Sm22a-PSEN1-KO group compared with .the percent of these measures in the WT group, indicating that PSEN1-KO resulted in .heart failure. The abnormally regulated genes resulted from PSEN1-KO were detected .to be enriched in muscle development and dilated cardiomyopathy. Among them, .several genes encode Ca2+ ion channels, promoting us to investigate the effects of .PSEN1 KO on regulation of Ca2+ in isolated adult cardiomyocytes. Consistently, in .isolated adult cardiomyocytes, PSEN1-KO increased the concentration of cytosolic .Ca2+ and reduced Ca2+ concentration inside the sarcoplasmic reticulum (SR) lumen at .the resting stage. Additionally, SR Ca2+ was decreased in the failing hearts of WT .mice, but with the lowest levels observed in the failing hearts of PSEN1 knockout .mice. These results indicate that the process of Ca2+ release from SR into cytoplasm.was affected by PSEN1 KO. Therefore, the abnormalities in Ca2+ homeostasis .resulted from downregulation of PSEN1 in failing hearts might contribute to agingrelated cardiomyopathy, which might had important implications for the treatment of aging-related heart diseases.
