title: Dynamin-2 mediates heart failure by modulating Ca2+ -dependent cardiomyocyte apoptosis.
abstract: BACKGROUND
  Heart 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.
  
  
  RESULTS
  Here, 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 Ca(2+) overload and subsequent mitochondria-dependent apoptosis. These events were preceded by enhanced membrane translocation of the L-type Ca(2+) channel due to DNM2 deficiency-mediated membrane trafficking dysfunction. Furthermore, prevention of cardiomyocyte Ca(2+)-mishandling largely ameliorated the DNM2 deficiency-associated cardiomyocyte apoptosis and HF.
  
  
  CONCLUSIONS
  DNM2 mediates HF by modulating Ca(2+)-dependent apoptotic death of cardiomyocyte. The finding may shed light on the new strategy of HF treatment.
authors: Key Laboratory of Basic Research in Cardiology of Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Institute of Medical Genetics, Tongji University, Shanghai 200120, China.
authors: Jun
authors: J
authors: Li
authors: Da-Sheng
authors: DS
authors: Zhang
authors: Jiang-Chuan
authors: JC
authors: Ye
authors: Chang-Ming
authors: CM
authors: Li
authors: Man
authors: M
authors: Qi
authors: Dan-Dan
authors: DD
authors: Liang
authors: Xin-Ran
authors: XR
authors: Xu
authors: Liang
authors: L
authors: Xu
authors: Yi
authors: Y
authors: Liu
authors: Hong
authors: H
authors: Zhang
authors: Yang-Yang
authors: YY
authors: Zhang
authors: Fang-Fei
authors: FF
authors: Deng
authors: Jing
authors: J
authors: Feng
authors: Dan
authors: D
authors: Shi
authors: Jin-Jin
authors: JJ
authors: Chen
authors: Li
authors: L
authors: Li
authors: Gang
authors: G
authors: Chen
authors: Yun-Fu
authors: YF
authors: Sun
authors: Lu-Ying
authors: LY
authors: Peng
authors: Yi-Han
authors: YH
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D034285:Dynamin II / Q000096:biosynthesis / Q000235:genetics*; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D015027:Zebrafish / Q000196:embryology
chemical_list: D020746:Calcium Channels, L-Type; D004247:DNA; D034285:Dynamin II; D002118:Calcium
keywords: Apoptosis; Ca(2+) overload; Dynamin; Heart failure; L-type calcium channel