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. 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 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.
BACKGROUND:A20 was originally characterized as a tumornecrosis 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. METHODS AND RESULTS: We investigated the role of constitutive humanA20 expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the humanA20 gene under the control of the alpha-myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in A20transgenic 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.
Authors: Hongliang Li; Chengwei He; Jinhua Feng; Yan Zhang; Qizhu Tang; Zhouyan Bian; Xue Bai; Heng Zhou; Hong Jiang; Scott P Heximer; Mu Qin; He Huang; Peter P Liu; Congxin Huang Journal: Proc Natl Acad Sci U S A Date: 2010-07-19 Impact factor: 11.205
Authors: Jens Lutz; Le A Luong; Matthias Strobl; Meihong Deng; Hai Huang; Martina Anton; Mustafa Zakkar; Karine Enesa; Hera Chaudhury; Dorian O Haskard; Marcus Baumann; Joseph Boyle; Sarah Harten; Patrick H Maxwell; Charles Pusey; Uwe Heemann; Paul C Evans Journal: J Mol Med (Berl) Date: 2008-09-24 Impact factor: 4.599
Authors: Madhu V Singh; Ann Kapoun; Linda Higgins; William Kutschke; Joshua M Thurman; Rong Zhang; Minati Singh; Jinying Yang; Xiaoqun Guan; John S Lowe; Robert M Weiss; Kathy Zimmermann; Fiona E Yull; Timothy S Blackwell; Peter J Mohler; Mark E Anderson Journal: J Clin Invest Date: 2009-03-09 Impact factor: 14.808