Matrix metalloproteinase inhibitors attenuate endotoxemia induced cardiac dysfunction: a potential role for MMP-9.
Enhanced cardiac generation of peroxynitrite contributes to septic cardiomyopathy. Since matrix metalloproteinases (MMPs) are activated in vitro by peroxynitrite, we hypothezised that MMPs may contribute to cardiac mechanical dysfunction in sepsis. Rats were injected (i.p.) with either lipopolysaccharide (LPS, 4 mg/kg) or vehicle. MMP inhibitors, either Ro 31-9790 (20 mg/kg), doxycycline (4 mg/kg), or vehicle were administered i.p. 30 min after LPS. At 6 h, when the symptoms of endotoxemia peak, hearts were excised and perfused as working hearts with Krebs-Henseleit buffer at 37 degrees C. Cardiac work (cardiac output x peak systolic pressure product) was measured. Perfusate and ventricle samples were analyzed by gelatin zymography to quantify MMP activity. Cardiac function was significantly depressed in LPS-treated rats compared to control rats (control: 55 +/- 4, LPS: 26 +/- 6 mmHg*mL*min(-1)). LPS also caused a loss of 72 kDa MMP-2 activity in the ventricles and the perfusate. Although MMP-9 activity was not detected in the ventricles, LPS resulted in an increase in perfusate 92 kDa MMP-9 activity. The MMP inhibitors significantly improved cardiac function of LPS-treated rats (Ro 31-9790: 38 +/- 3, doxycycline: 51 +/- 3 mmHg*mL*min(-1)), had no effect on the loss of MMP-2 activity, and significantly reduced the MMP-9 activity in the perfusate. These results demonstrate, for the first time, that LPS induced cardiac dysfunction is associated with a loss in ventricular MMP-2 activity and the release of MMP-9 from the heart. MMP inhibitors can significantly preserve cardiac mechanical function during septic shock.
Department of Pharmacology, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada.
Manoj M
MM
Lalu
Cindy Q
CQ
Gao
Richard
R
Schulz
D000818:Animals; D001794:Blood Pressure; D002302:Cardiac Output; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004318:Doxycycline / Q000008:administration & dosage / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D019446:Endotoxemia / Q000188:drug therapy*; D004789:Enzyme Activation; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000627:therapeutic use*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; C097661:Ro 31-9790; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline