TY - JOUR
T1 - Transgenic overexpression of matrix metalloproteinase-9 in macrophages attenuates the inflammatory response and improves left ventricular function post-myocardial infarction
AU - Zamilpa, Rogelio
AU - Ibarra, Jessica
AU - de Castro Brás, Lisandra E.
AU - Ramirez, Trevi A.
AU - Nguyen, Nguyen
AU - Halade, Ganesh V.
AU - Zhang, Jianhua
AU - Dai, Qiuxia
AU - Dayah, Tariq
AU - Chiao, Ying Ann
AU - Lowell, Wesley
AU - Ahuja, Seema S.
AU - D'Armiento, Jeanine
AU - Jin, Yu Fang
AU - Lindsey, Merry L.
N1 - Funding Information:
We acknowledge support from T32 ( HL07446 ), American Heart Association ( 09POST2150178 ), and HL075360S1 to RZ; NSF 0649172 , NIH EB009496 , and NIH 1SC2 HL101430 to Y-FJ; and from NHLBI HHSN 268201000036C ( N01-HV-00244 ) for the San Antonio Cardiovascular Proteomics Center and R01 HL075360 , the Max and Minnie Tomerlin Voelcker Fund , and the Veteran's Administration (Merit) to MLL.
PY - 2012/11
Y1 - 2012/11
N2 - Following myocardial infarction (MI), activated macrophages infiltrate into the necrotic myocardium as part of a robust pro-inflammatory response and secrete matrix metalloproteinase-9 (MMP-9). Macrophage activation, in turn, modulates the fibrotic response, in part by stimulating fibroblast extracellular matrix (ECM) synthesis. We hypothesized that overexpression of human MMP-9 in mouse macrophages would amplify the inflammatory and fibrotic responses to exacerbate left ventricular dysfunction. Unexpectedly, at day 5 post-MI, ejection fraction was improved in transgenic (TG) mice (25 ± 2%) compared to the wild type (WT) mice (18 ± 2%; p < 0.05). By gene expression profiling, 23 of 84 inflammatory genes were decreased in the left ventricle infarct (LVI) region from the TG compared to WT mice (all p < 0.05). Concomitantly, TG macrophages isolated from the LVI, as well as TG peritoneal macrophages stimulated with LPS, showed decreased inflammatory marker expression compared to WT macrophages. In agreement with attenuated inflammation, only 7 of 84 cell adhesion and ECM genes were increased in the TG LVI compared to WT LVI, while 43 genes were decreased (all p < 0.05). These results reveal a novel role for macrophage-derived MMP-9 in blunting the inflammatory response and limiting ECM synthesis to improve left ventricular function post-MI.
AB - Following myocardial infarction (MI), activated macrophages infiltrate into the necrotic myocardium as part of a robust pro-inflammatory response and secrete matrix metalloproteinase-9 (MMP-9). Macrophage activation, in turn, modulates the fibrotic response, in part by stimulating fibroblast extracellular matrix (ECM) synthesis. We hypothesized that overexpression of human MMP-9 in mouse macrophages would amplify the inflammatory and fibrotic responses to exacerbate left ventricular dysfunction. Unexpectedly, at day 5 post-MI, ejection fraction was improved in transgenic (TG) mice (25 ± 2%) compared to the wild type (WT) mice (18 ± 2%; p < 0.05). By gene expression profiling, 23 of 84 inflammatory genes were decreased in the left ventricle infarct (LVI) region from the TG compared to WT mice (all p < 0.05). Concomitantly, TG macrophages isolated from the LVI, as well as TG peritoneal macrophages stimulated with LPS, showed decreased inflammatory marker expression compared to WT macrophages. In agreement with attenuated inflammation, only 7 of 84 cell adhesion and ECM genes were increased in the TG LVI compared to WT LVI, while 43 genes were decreased (all p < 0.05). These results reveal a novel role for macrophage-derived MMP-9 in blunting the inflammatory response and limiting ECM synthesis to improve left ventricular function post-MI.
KW - Cardiac remodeling
KW - Extracellular matrix
KW - Inflammation
KW - Macrophage
KW - Matrix metalloproteinase-9
KW - Myocardial infarction
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U2 - 10.1016/j.yjmcc.2012.07.017
DO - 10.1016/j.yjmcc.2012.07.017
M3 - Article
C2 - 22884843
AN - SCOPUS:84867403208
SN - 0022-2828
VL - 53
SP - 599
EP - 608
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 5
ER -