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ZIRC
ZFIN ID: ZDB-PUB-130308-7
Dynamin-2 mediates heart failure by modulating Ca(2+) -dependent cardiomyocyte apoptosis
Li, J., Zhang, D.S., Ye, J.C., Li, C.M., Qi, M., Liang, D.D., Xu, X.R., Xu, L., Liu, Y., Zhang, H., Zhang, Y.Y., Deng, F.F., Feng, J., Shi, D., Chen, J.J., Li, L., Chen, G., Sun, Y.F., Peng, L.Y., and Chen, Y.H.
Date: 2013
Source: International Journal of Cardiology   168(3): 2109-19 (Journal)
Registered Authors: Li, Jun, Li, Li
Keywords: heart failure, dynamin, apoptosis, Ca2 + overload, L-type calcium channel
MeSH Terms:
  • Animals
  • Apoptosis*
  • Blotting, Western
  • Calcium/metabolism*
  • Calcium Channels, L-Type/metabolism*
  • DNA/genetics*
  • Disease Models, Animal
  • Dynamin II/biosynthesis
  • Dynamin II/genetics*
  • Heart Failure/genetics*
  • Heart Failure/metabolism
  • Heart Failure/pathology
  • Humans
  • In Situ Nick-End Labeling
  • Microscopy, Electron, Transmission
  • Mitochondria, Heart/metabolism
  • Mitochondria, Heart/ultrastructure
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/ultrastructure*
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Sarcoplasmic Reticulum/metabolism
  • Sarcoplasmic Reticulum/ultrastructure
  • Zebrafish/embryology
PubMed: 23410488 Full text @ Int. J. Cardiol.
FIGURES
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.

Methods and 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 Ca2 + overload and subsequent mitochondria-dependent apoptosis. These events were preceded by enhanced membrane translocation of the L-type Ca2 + channel due to DNM2 deficiency-mediated membrane trafficking dysfunction. Furthermore, prevention of cardiomyocyte Ca2 +-mishandling largely ameliorated the DNM2 deficiency-associated cardiomyocyte apoptosis and HF.

Conclusions

DNM2 mediates HF by modulating Ca2 +-dependent apoptotic death of cardiomyocyte. The finding may shed light on the new strategy of HF treatment.

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