Published Online
on March 26, 2007

A more recent version of this article appeared on April 10, 2007

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Submitted on August 5, 2006
Accepted on December 29, 2006

Targeted Cardiac Overexpression of A20 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction

Hong-Liang Li MD, PhD, Ming-Lei Zhuo BSc, Dong Wang MD, Ai-Bing Wang PhD, Hua Cai PhD, Li-Hong Sun MSc, Qinglin Yang PhD, Yue Huang PhD, Yu-Sheng Wei PhD, Peter P. Liu MD, De-Pei Liu PhD^*, and Chih-Chuan Liang PhD

From the National Laboratory of Medical Molecular Biology (H.-L.L, M.-L.Z., A.-B.W., L.-H.S., Y.H., Y.-S.W., D.-P.L., C.-C.L) and Department of Anatomy, Histology, and Embryology (D.W.), Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Section of Cardiology (H.C.), Department of Medicine, Division of Biological Sciences and Pritzker School of Medicine, University of Chicago, Chicago, Ill; Cardiovascular Research Institute (Q.Y.), Morehouse School of Medicine, Atlanta, Ga; and Heart and Stroke/Richard Lewar Centre of Excellence (P.P.L). University Health Network, University of Toronto, Toronto, Ontario, Canada.

^* To whom correspondence should be addressed. E-mail: liudp{at}pumc.edu.cn.

Background--A20 was originally characterized as a tumor necrosis factor-inducible gene in human umbilical vein endothelial cells. As an inhibitor of nuclear factor-B signaling, A20 protects against apoptosis, inflammation, and cardiac hypertrophy. In the present study, we tested the hypothesis that cardiac-specific overexpression of A20 could protect the heart from myocardial infarction.

Methods and Results--We investigated the role of constitutive human A20 expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the human A20 gene under the control of the -myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in A20 transgenic mice and control animals. The extent of infarction was then quantified by 2-dimensional and M-mode echocardiography and by molecular and pathological analyses of heart samples in infarct and remote heart regions 7 days after myocardial infarction. Constitutive overexpression of A20 in the murine heart resulted in attenuated infarct size and improved cardiac function 7 days after myocardial infarction. Significantly, we found a decrease in nuclear factor-B signaling and apoptosis, as well as proinflammatory response, cardiac remodeling, and interstitial fibrosis, in noninfarct regions in the hearts of constitutive A20-expressing animals compared with control animals.

Conclusions--Cardiac-specific overexpression of A20 improves cardiac function and inhibits cardiac remodeling, apoptosis, inflammation, and fibrosis after acute myocardial infarction.

Key words: apoptosis • cardiovascular diseases • fibrosis • gene therapy • hypertrophy • inflammation • remodeling

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