Effect of matrix metalloproteinase inhibition by doxycycline on myocardial healing and remodeling after myocardial infarction.
The aim of conducting this study was to assess the clinical relevance of matrix metalloproteinase (MMP) inhibition by doxycycline, an effective MMP inhibitor, in a rat model of extensive myocardial infarction (MI) and left ventricular (LV) dysfunction. Rats (n = 22) were subjected to extensive anterior MI. Doxycycline (25 mg SC, daily) or saline (control) injections were started for nine days thereafter. The effect of doxycycline on MMP activity in the infarcted and remote myocardium was measured by zymography, in another subgroup (n = 8), nine days after MI. Echocardiography and magnetic resonance imaging (MRI) studies were performed at one and thirty days after MI to assess LV remodeling and function. After 4 weeks, hearts were fixed, and subjected to morphometric and histological analysis. Compared with control, doxycycline treatment attenuated MMP-9 and -2 activity in both infarcted and remote myocardium. Serial echocardiography studies showed that doxycycline failed to attenuate scar thinning, LV dilatation and dysfunction. MRI study showed that doxycycline impaired LV compensatory hypertrophy. Furthermore, compared with control, doxycycline reduced vessel density (/mm(2) +/- SEM) in the infarcted myocardium (84 +/- 16 vs. 46 +/- 9/mm(2), respectively; p < 0.05). Our work suggest that effective MMPs' inhibition in the infarcted and remote myocardium by doxycycline does not prevent LV remodeling and dysfunction but impairs angiogenesis and compensatory LV hypertrophy. Our findings caution against aggressive, non-selective inhibition of MMPs in the early healing phase after MI.
Tessone
Ariel
A
Neufeld Cardiac Research Institute, Sheba Medical Center, Tel-Aviv University, Tel Hashomer, Israel.
Feinberg
Micah S
MS
Barbash
Israel M
IM
Reich
Reuven
R
Holbova
Radka
R
Richmann
Michal
M
Mardor
Yael
Y
Leor
Jonathan
J
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage* / Q000494:pharmacology; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006321:Heart / Q000000981:diagnostic imaging; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008279:Magnetic Resonance Imaging; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D020257:Ventricular Remodeling / Q000187:drug effects*; D014945:Wound Healing / Q000187:drug effects*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D004318:Doxycycline