Involvement of death receptor signaling in mechanical stretch-induced cardiomyocyte apoptosis.
Recent evidences suggest that mechanical overload associated with abnormal blood pressure causes apoptosis in cardiovascular system. Still, the intracellular signaling leading to cardiomyocyte apoptosis has not been fully defined. Previous reports ascribed stretch-induced cardiomyocyte apoptosis to rennin-angiotensin-system (RAS) signaling and/or mitochondria-dependent apoptosis pathway. The present study shows the involvement of death receptor signaling in mechanical stretch-induced cardiomyocyte apoptosis. By employing a well-described in vitro stretch model, we studied stretch-induced apoptosis and found that the death receptor-mediated apoptotic signaling was activated in stretch-induced apoptosis in neonatal rat cardiomyocytes. The major finding are as following: (1) The mechanical stretch activated death receptor-mediated apoptotic signaling in cardiomyocytes, including activation of caspases 8, 9 and 3, up-regulation of Fas, FasL expression and cell surface trafficking of death ligands (FasL and TRAIL); (2) That exogenous death ligand (TRAIL) enhanced, while soluble death receptor (sDR5) neutralized, stretch-induced apoptosis; (3) Adenovirus-delivered dominant negative FADD (FADD-DN) significantly reduced apoptosis, caspases 8, 9, and 3 activation, and stretch-induced cyt c release from mitochondria. These data clearly suggested mechanical stretch activated death receptor-mediated apoptotic signaling in cardiomyocytes. In conclusion, our data suggest that the FADD-linked death receptor signaling may contribute to stretch-induced cardiomyocyte apoptosis, probably through activating mitochondria-dependent apoptotic signaling.
Liao
Xudong
X
Cardiovascular Institute and Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100037, P.R. China.
Wang
Xiaohui
X
Gu
Ying
Y
Chen
Quan
Q
Chen
Lan-Ying
LY
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505644:Tnfrsf10b protein, rat; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha