TY - JOUR
T1 - Transgenic expression of matrix metalloproteinase-9 modulates collagen deposition in a mouse model of atherosclerosis
AU - Lemaître, Vincent
AU - Kim, Henry E.
AU - Forney-Prescott, Margaret
AU - Okada, Yasunori
AU - D'Armiento, Jeanine
N1 - Funding Information:
We thank Dr. Alan Tall (Columbia University) for reading the manuscript and Dr. Takayuki Shiomi (Columbia University) for his precious help. This work was supported by American Heart Association grant in aid 9850025T (J.D.), American Heart Association post-doctoral fellowship 0020232T (V.L.) and American Heart Association scientific development grant 0535405T (V.L.).
PY - 2009/7
Y1 - 2009/7
N2 - Matrix metalloproteinase-9 (MMP-9) has been proposed to be an important modulator of atherosclerotic plaque vulnerability. We generated a transgenic (tg) model expressing human proMMP-9 in macrophages, using the scavenger receptor enhancer/promoter A. This model was crossed into the double Apoe/Timp-1 knockout background. After 16 weeks of a high-fat diet, there were no significant changes in plaque size in the proximal aortas between the four groups of the study population (Apoe-/-, Apoe-/-/MMP-9tg, Apoe-/-/Timp-1-/-, and Apoe-/-/MMP-9tg/Timp-1-/-), and, in the Timp-1 knockout background, MMP-9 transgenic mice and control littermates had similar micro-aneurysm formation. However, lesions in Apoe-/-/MMP-9tg/Timp-1-/- mice contained significantly more collagen compared to the three other groups (P < 0.005). Culture supernatants from elicited Apoe-/-/MMP-9tg/Timp-1-/- macrophages contained higher levels of active TGF-β than the three other groups (P < 0.05), suggesting that augmented collagen deposition resulted from an increase in TGF-β activation due to transgenic MMP-9 in the Timp-1-/- background. This study indicates that, in human atherosclerosis, increased MMP-9 activity could up-regulate collagen deposition, possibly through TGF-β activation.
AB - Matrix metalloproteinase-9 (MMP-9) has been proposed to be an important modulator of atherosclerotic plaque vulnerability. We generated a transgenic (tg) model expressing human proMMP-9 in macrophages, using the scavenger receptor enhancer/promoter A. This model was crossed into the double Apoe/Timp-1 knockout background. After 16 weeks of a high-fat diet, there were no significant changes in plaque size in the proximal aortas between the four groups of the study population (Apoe-/-, Apoe-/-/MMP-9tg, Apoe-/-/Timp-1-/-, and Apoe-/-/MMP-9tg/Timp-1-/-), and, in the Timp-1 knockout background, MMP-9 transgenic mice and control littermates had similar micro-aneurysm formation. However, lesions in Apoe-/-/MMP-9tg/Timp-1-/- mice contained significantly more collagen compared to the three other groups (P < 0.005). Culture supernatants from elicited Apoe-/-/MMP-9tg/Timp-1-/- macrophages contained higher levels of active TGF-β than the three other groups (P < 0.05), suggesting that augmented collagen deposition resulted from an increase in TGF-β activation due to transgenic MMP-9 in the Timp-1-/- background. This study indicates that, in human atherosclerosis, increased MMP-9 activity could up-regulate collagen deposition, possibly through TGF-β activation.
KW - Collagen
KW - Matrix metalloproteinase
KW - Mouse model of atherosclerosis
UR - http://www.scopus.com/inward/record.url?scp=67349160215&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349160215&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2008.11.030
DO - 10.1016/j.atherosclerosis.2008.11.030
M3 - Article
C2 - 19144335
AN - SCOPUS:67349160215
VL - 205
SP - 107
EP - 112
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
IS - 1
ER -