Inhibition of Fas-Associated Death Domain-Containing Protein (FADD) Protects against Myocardial Ischemia/Reperfusion Injury in a Heart Failure Mouse Model.

Authors

Qian Fan, Center for Translational Medicine, Temple University School of Medicine; Department of Gerontology, Beijing Chaoyang Hospital-Affiliate of Beijing Capital Medical University, Beijing, ChinaFollow
Zheng M Huang, Center for Translational Medicine, Temple University School of Medicine
Matthieu Boucher, Center for Translational Medicine, Temple University School of Medicine
Xiying Shang, Center for Translational Medicine, Temple University School of MedicineFollow
Lin Zuo, Center for Translational Medicine, Temple University School of MedicineFollow
Henriette Brinks, Center for Translational Medicine, Temple University School of Medicine
Wayne Bond Lau, Department of Emergency Medicine, Thomas Jefferson University HospitalFollow
Jianke Zhang, Department of Microbiology and Immunology, Thomas Jefferson UniversityFollow
J Kurt Chuprun, Center for Translational Medicine, Temple University School of MedicineFollow
Erhe Gao, Center for Translational Medicine, Temple University School of MedicineFollow

Document Type

Article

Publication Date

9-13-2013

Comments

This article has been peer reviewed and is published in PloS One.

Volume 8, Issue 9, 13 September 2013, Article numbere73537.

The published version is available at DOI: 10.1371/journal.pone.0073537.

© 2013 Fan et al.

Abstract

AIM: 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.

CONCLUSION: 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.

Recommended Citation

Fan, Qian; Huang, Zheng M; Boucher, Matthieu; Shang, Xiying; Zuo, Lin; Brinks, Henriette; Lau, Wayne Bond; Zhang, Jianke; Chuprun, J Kurt; and Gao, Erhe, "Inhibition of Fas-Associated Death Domain-Containing Protein (FADD) Protects against Myocardial Ischemia/Reperfusion Injury in a Heart Failure Mouse Model." (2013). Department of Emergency Medicine Faculty Papers. Paper 23.
https://jdc.jefferson.edu/emfp/23

PubMed ID

24058479