Ostreolysin induces sustained contraction of porcine coronary arteries and endothelial dysfunction in middle- and large-sized vessels.
Ostreolysin (Oly), a cytolytic and cardiotoxic protein from the oyster mushroom (Pleurotus ostreatus), is lethal for mice with an LD(50) of 1170 microg/kg following intravenous application. Its cardiotoxicity is associated with hyperkalemia, which is probably a consequence of potassium released from the lysed cells. Moreover, sub-micromolar concentrations of Oly induce a concentration-dependent increase in rat aortic ring tension, suggesting that ischaemia, and consequent hypoxic injury of cardiomyocytes, could also derive from vasospasm induced by this toxic protein. The purpose of the present study was to demonstrate histopathological lesions caused by Oly after parenteral application to rats, and to define the mechanisms of Oly-induced vasoconstriction using inhibitors verapamil, lanthanum chloride, and selective endothelin receptor antagonist TBC3214, which have different molecular targets, in vitro on porcine coronary artery rings. We found that Oly causes endothelial injury with perivascular oedema in the heart and lungs, as well as myocardial haemorrhages in rats. Treatment of porcine coronary artery rings with Oly causes concentration-dependent vasoconstriction and prevents endothelium-mediated relaxation. Using TBC3214 as a selective blocker of the endothelin A receptor, we showed that vasoconstriction induced by Oly was independent of endothelin release and its effects. Verapamil (1 microM) greatly reduced Oly-evoked contractions of porcine coronary artery rings, while lanthanum abolished them completely. These results provide evidence that the contraction of coronary arteries by Oly is due mainly to the increased influx of Ca(2+) from the extracellular space through voltage-dependent L-type Ca(2+) channels and cation non-selective channels. Experiments suggest that Oly damages endothelial cells both in vitro and in vivo, and probably exhibits direct contractile effects on coronary smooth muscle cells.
Juntes
Polona
P
Institute of Pathology, Forensic and Administrative Veterinary Medicine, Veterinary Faculty, University of Ljubljana, Gerbiceva 60, 1000 Ljubljana, Slovenia.
Rebolj
Katja
K
Sepcić
Kristina
K
Macek
Peter
P
Zuzek
Monika Cecilija
MC
Cestnik
Vojteh
V
Frangez
Robert
R
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005656:Fungal Proteins / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000494:pharmacology*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D007811:Lanthanum / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology
D005656:Fungal Proteins; D006460:Hemolysin Proteins; D007555:Isoxazoles; D013449:Sulfonamides; C424912:TBC 3214; C461280:ostreolysin; C028521:lanthanum chloride; D007811:Lanthanum; D014700:Verapamil