Targeted cardiac overexpression of A20 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction.
BACKGROUND
A20 was originally characterized as a tumor necrosis factor-inducible gene in human umbilical vein endothelial cells. As an inhibitor of nuclear factor-kappaB 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.


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 alpha-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-kappaB 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.
Li
Hong-Liang
HL
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, PR China.
Zhuo
Ming-Lei
ML
Wang
Dong
D
Wang
Ai-Bing
AB
Cai
Hua
H
Sun
Li-Hong
LH
Yang
Qinglin
Q
Huang
Yue
Y
Wei
Yu-Sheng
YS
Liu
Peter P
PP
Liu
De-Pei
DP
Liang
Chih-Chuan
CC
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000097:blood; D004268:DNA-Binding Proteins; D005355:Fibrosis; D005813:Genes, Synthetic; D006352:Heart Ventricles / Q000503:physiopathology*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000517:prevention & control*; D051550:I-kappa B Kinase / Q000032:analysis; D007249:Inflammation / Q000209:etiology; D018836:Inflammation Mediators / Q000032:analysis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D045265:Natriuretic Peptides / Q000032:analysis; D009504:Neutrophils / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D016037:Single-Blind Method; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000517:prevention & control*; D024723:Ventricular Myosins / Q000235:genetics; D020257:Ventricular Remodeling / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D045265:Natriuretic Peptides; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D024723:Ventricular Myosins