Parstatin: a cryptic peptide involved in cardioprotection after ischaemia and reperfusion injury.
OBJECTIVE
Thrombin activates protease-activated receptor 1 by proteolytic cleavage of the N-terminus. Although much research has focused on the activated receptor, little is known about the 41-amino acid N-terminal peptide (parstatin). We hypothesized that parstatin would protect the heart against ischaemia-reperfusion injury.


RESULTS
We assessed the protective role of parstatin in an in vivo and in vitro rat model of myocardial ischaemia-reperfusion injury. Parstatin treatment before, during, and after ischaemia decreased infarct size by 26%, 23%, and 18%, respectively, in an in vivo model of ischaemia-reperfusion injury. Parstatin treatment immediately before ischaemia decreased infarct size by 65% and increased recovery in ventricular function by 23% in an in vitro model. We then assessed whether parstatin induced cardioprotection by activation of a Gi-protein-dependent pathway. Gi-protein inactivation by pertussis toxin completely abolished the cardioprotective effects. The cardioprotective effects were also abolished by inhibition of nitric oxide synthase (NOS), extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and K(ATP) channels in vitro. Furthermore, parstatin increased coronary flow and decreased perfusion pressure in the isolated heart. The vasodilatory properties of parstatin were confirmed in rat coronary arterioles.


CONCLUSIONS
A single treatment of parstatin administered prior to ischaemia confers immediate cardioprotection by recruiting the Gi-protein activation pathway including p38 MAPK, ERK1/2, NOS, and K(ATP) channels. Parstatin exerts effects on both the cardiomyocytes and the coronary circulation to induce cardioprotection. This suggests a potential therapeutic role of parstatin in the treatment of cardiac injury resulting from ischaemia and reperfusion.
Strande
Jennifer L
JL
Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, USA. jstrande@mcw.edu
Widlansky
Michael E
ME
Tsopanoglou
Nikos E
NE
Su
Jidong
J
Wang
JingLi
J
Hsu
Anna
A
Routhu
Kasi V
KV
Baker
John E
JE
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044463:Receptor, PAR-1 / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D054086:KATP Channels; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D044463:Receptor, PAR-1; D018160:Receptors, Cytoplasmic and Nuclear; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase