TY - JOUR
T1 - Effect of matrix metalloproteinase inhibition by doxycycline on myocardial healing and remodeling after myocardial infarction
AU - Tessone, Ariel
AU - Feinberg, Micah S.
AU - Barbash, Israel M.
AU - Reich, Reuven
AU - Holbova, Radka
AU - Richmann, Michal
AU - Mardor, Yael
AU - Leor, Jonathan
PY - 2005/12
Y1 - 2005/12
N2 - 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 (/mm2 ± SEM) in the infarcted myocardium (84 ± 16 vs. 46 ± 9/mm2, 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.
AB - 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 (/mm2 ± SEM) in the infarcted myocardium (84 ± 16 vs. 46 ± 9/mm2, 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.
KW - Angiogenesis
KW - Heart failure
KW - Myocytes
KW - Remodeling
UR - http://www.scopus.com/inward/record.url?scp=32444441006&partnerID=8YFLogxK
U2 - 10.1007/s10557-005-5201-6
DO - 10.1007/s10557-005-5201-6
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C2 - 16435072
AN - SCOPUS:32444441006
SN - 0920-3206
VL - 19
SP - 383
EP - 390
JO - Cardiovascular Drugs and Therapy
JF - Cardiovascular Drugs and Therapy
IS - 6
ER -