Cardioprotection by the phytoestrogen genistein in experimental myocardial ischaemia-reperfusion injury.
1. Soybean phytoestrogens have no oestrogen agonist effects on the reproductive system and therefore it is reasonable to explore the potential of these naturally occurring plant oestrogens in the cardiovascular pathology. We therefore investigated the effects of genistein in a rat model of myocardial ischaemia-reperfusion injury. 2. Anaesthetized rats were subjected to total occlusion (45 min) of the left main coronary artery followed by 5 h reperfusion (MI/R). Sham operated rats were used as controls. Myocardial necrosis, myocardial myeloperoxidase activity (MPO), serum creatinine phosphokinase activity (CPK), serum and macrophage Tumour Necrosis Factor-alpha (TNF-alpha), cardiac intercellular adhesion molecule-1 (ICAM-1) immunostaining, cardiac mRNA for ICAM-1 evaluated by the means of reverse transcriptase polymerase chain reaction (RT - PCR), ventricular arrhythmias and myocardial contractility (left ventricle dP/dt(max)) were evaluated. 3. Myocardial ischaemia and reperfusion in untreated rats produced marked myocardial necrosis, increased serum CPK activity and MPO activity both in the area-at-risk and in the necrotic area, reduced myocardial contractility, caused ventricular arrhythmias and induced a marked increase in serum and macrophage TNF-alpha. Furthermore myocardial ischaemia-reperfusion injury increased ICAM-1 expression in the myocardium. 4. Administration of genistein (1 mg kg(-1), i.v., 5 min after coronary artery occlusion) lowered myocardial necrosis and MPO activity in the area-at-risk and in the necrotic area, decreased serum CPK activity, increased myocardial contractility, decreased the occurrence of ventricular arrhythmias, reduced serum and macrophages levels of TNF-alpha and blunted ICAM-1 expression in the injured myocardium. Finally genistein added in vitro to peritoneal macrophages collected from untreated rats subjected to myocardial ischaemia-reperfusion injury significantly reduced TNF-alpha production. 5. Our data suggest that genistein limits the inflammatory response and protects against myocardial ischaemia-reperfusion injury.
Deodato
B
B
Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario, Via C. Valeria, Gazzi, 98125 Messina, Italy.
Altavilla
D
D
Squadrito
G
G
Campo
G M
GM
Arlotta
M
M
Minutoli
L
L
Saitta
A
A
Cucinotta
D
D
Calapai
G
G
Caputi
A P
AP
Miano
M
M
Squadrito
F
F
D000818:Animals; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D010052:Ovariectomy; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D002317:Cardiovascular Agents; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019833:Genistein; D009195:Peroxidase; D003402:Creatine Kinase