Protection from cardiac injury by induction of heme oxygenase-1 and nitric oxide synthase in a focal ischaemia-reperfusion model.
The enzymes heme oxygenase (HO) generate carbon monoxide (CO) in living organisms during heme degradation. Carbon monoxide has recently been shown to dilate blood vessels and to possess anti-inflammatory properties. It is also known that nitric oxide (NO) donors ameliorate cardiac ischaemia-reperfusion injury in experimental models of global or focal ischaemia-reperfusion (FIR). The two gaseous mediators share the same mechanism of action via the stimulation of soluble guanylyl cyclase and the increase in cellular levels of cyclic GMP. We studied the effects of manipulating the HO system and the possible interaction between CO and NO in an experimental in vivo model of FIR in the rat heart. FIR-subjected rats had necrotic area in the left ventricle, ventricular arrhythmias and a shortening of survival time in comparison to sham-operated animals. Resident mast cells underwent a heavy degranulation, malonyldialdehyde was produced by myocardial cell membranes, and tissue calcium levels were increased. High levels of myeloperoxidase were also detected, suggesting a FIR-related inflammatory process. In animals pre-treated with the HO-1 inducer, hemin, all the biochemical and morphometric markers of FIR were minimized or fully abated. Consistently, the biochemical and morphometric markers of FIR were reversed in rats treated with the HO-1 blocker, ZnPP-IX, prior to hemin administration. Pre-treatment with hemin significantly increases the expression and activity of both cardiac HO-1 and iNOS, suggesting that CO and NO cooperate in the cardioprotective effect against FIR-induced damage, and that there is a therapeutic synergism between NO-donors and CO-releasing molecules, via the common stimulation of increase in cGMP levels and decrease in calcium overload.
Giannini
L
L
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
Vannacci
A
A
Fabrizi
F
F
Uliva
C
C
Bani
D
D
Masini
E
E
Mannaioni
P F
PF
D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004790:Enzyme Induction; D006335:Heart Injuries / Q000201:enzymology* / Q000473:pathology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008407:Mast Cells; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D013997:Time Factors
D008315:Malondialdehyde; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D006152:Cyclic GMP; D001663:Bilirubin; D002118:Calcium