Inhibition of Fas-associated death domain-containing protein (FADD) protects against myocardial ischemia/reperfusion injury in a heart failure mouse model.
OBJECTIVE
As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy in the treatment of heart failure.


METHODS
Cardiomyocyte-specific FADD knockout mice along with non-transgenic littermates (NLC) were subjected to 30 minutes myocardial ischemia followed by 7 days of reperfusion or 6 weeks of permanent myocardial ischemia via the ligation of left main descending coronary artery. Cardiac function were evaluated by echocardiography and left ventricular (LV) catheterization and cardiomyocyte death was measured by Evans blue-TTC staining, TUNEL staining, and caspase-3, -8, and -9 activities. In vitro, H9C2 cells transfected with ether scramble siRNA or FADD siRNA were stressed with chelerythrin for 30 min and cleaved caspase-3 was assessed.


RESULTS
FADD expression was significantly decreased in FADD knockout mice compared to NLC. Ischemia/reperfusion (I/R) upregulated FADD expression in NLC mice, but not in FADD knockout mice at the early time. FADD deletion significantly attenuated I/R-induced cardiac dysfunction, decreased myocardial necrosis, and inhibited cardiomyocyte apoptosis. Furthermore, in 6 weeks long term permanent ischemia model, FADD deletion significantly reduced the infarct size (from 41.20 ± 3.90% in NLC to 26.83 ± 4.17% in FADD deletion), attenuated myocardial remodeling, improved cardiac function and improved survival. In vitro, FADD knockdown significantly reduced chelerythrin-induced the level of cleaved caspase-3.


CONCLUSIONS
Taken together, our results suggest FADD plays a critical role in post-ischemic heart failure. Inhibition of FADD retards heart failure progression. Our data supports the further investigation of FADD as a potential target for genetic manipulation in the treatment of heart failure.
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America ; Department of Gerontology, Beijing Chaoyang Hospital-Affiliate of Beijing Capital Medical University, Beijing, China.
Qian
Q
Fan
Zheng M
ZM
Huang
Matthieu
M
Boucher
Xiying
X
Shang
Lin
L
Zuo
Henriette
H
Brinks
Wayne Bond
WB
Lau
Jianke
J
Zhang
J Kurt
JK
Chuprun
Erhe
E
Gao
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000601:surgery; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D053119:Benzophenanthridines; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D034741:RNA, Small Interfering; C016299:chelerythrine; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9