کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5976219 | 1576209 | 2013 | 11 صفحه PDF | دانلود رایگان |
BackgroundHeart failure (HF) is approaching an epidemic proportion and has become one of the leading causes of death. It imposes a great burden on the healthcare system and society. Remodeling of cardiomyocyte membranes has a profound role in the pathogenesis of HF. However, whether dynamin (DNM), a membrane-remodeling GTPase, is associated with HF remains unclear.Methods and resultsHere, we identified that DNM2 is necessary for the maintenance of cardiac function. Endogenous DNM2 protein levels were gradually decreased in parallel with the progression of HF in different experimental animal models. Decreased DNM2 level was also observed in the end-stage failing human heart. DNM2-deficient zebrafish exhibited signs of notable cardiac apoptosis and eventually developed severe HF. Mechanistic study showed that DNM2 downregulation caused cardiomyocyte sarcoplasmic reticulum Ca2Â + overload and subsequent mitochondria-dependent apoptosis. These events were preceded by enhanced membrane translocation of the L-type Ca2Â + channel due to DNM2 deficiency-mediated membrane trafficking dysfunction. Furthermore, prevention of cardiomyocyte Ca2Â +-mishandling largely ameliorated the DNM2 deficiency-associated cardiomyocyte apoptosis and HF.ConclusionsDNM2 mediates HF by modulating Ca2Â +-dependent apoptotic death of cardiomyocyte. The finding may shed light on the new strategy of HF treatment.
Journal: International Journal of Cardiology - Volume 168, Issue 3, 3 October 2013, Pages 2109-2119