Augmented healing process in female mice with acute myocardial infarction.
BACKGROUND
It is well established that premenopausal women are protected from cardiovascular disease. This gender difference in favor of females is also demonstrated in animal studies. Our research group previously found that female mice had much lower incidence of cardiac rupture and mortality than did males during the acute phase of myocardial infarction (MI); however, the mechanisms responsible for such protection are not fully understood.


OBJECTIVE
The aim of this study was to determine whether the favorable cardiac effect observed in female mice with MI is due to an augmented healing process that includes less inflammation, reduced matrix degradation, and enhanced neovascularization.


METHODS
Twelve-week-old male and female C57BL/6J mice were subjected to MI by ligating the left anterior descending coronary artery and then euthanized at 1, 4, 7, or 14 days post-MI. Inflammatory cell infiltration and myofibroblast transformation, matrix metalloproteinase (MMP)-2 and MMP-9 activity, tissue inhibitor of metalloproteinase (TIMP)-I expression, and neovascularization were examined by immunohistochemistry, zymography, Western blot, and laser scanning confocal microscopy, respectively. Cardiac function was evaluated by echocardiography on day 14.


RESULTS
We found that: (1) neutrophil infiltration during the early phase of MI (1-4 days) was much lower in females than in males and was associated with lower MMP-9 activity and higher TIMP-1 protein expression, indicating less-exaggerated inflammation and extracellular matrix degradation in females; (2) myofibroblast transformation, as indicated by expression of alpha-smooth muscle actin, was significantly greater in females than in males at day 7 of MI (P<0.05), indicating facilitated collagen deposition and scar formation; and (3) neovascularization (vascular area in the infarct border) was markedly increased in females, and was associated with better preserved cardiac function and less left ventricular dilatation.


CONCLUSIONS
Our data suggest that less-exaggerated early inflammation and augmented reparative fibrotic response, indicated by enhanced myofibroblast transformation, may contribute greatly to low rupture rates in females during the acute and subacute phases of MI, whereas enhanced neovascularization may lead to better preserved cardiac function post-MI.
Wang
Fangfei
F
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, and Department of Biology, Wayne State University, Detroit, Michigan 48202-2689, USA.
Keimig
Thomas
T
He
Quan
Q
Ding
Jennifer
J
Zhang
Zhenggang
Z
Pourabdollah-Nejad
Siamak
S
Yang
Xiao-Ping
XP
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D004452:Echocardiography; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000503:physiopathology*; D009389:Neovascularization, Pathologic; D020556:Neutrophil Infiltration; D020127:Recovery of Function; D012737:Sex Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D020257:Ventricular Remodeling
D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9