PT  - JOURNAL ARTICLE
AU  - Kasi V. Routhu
AU  - Nikos E. Tsopanoglou
AU  - Jennifer L. Strande
TI  - Parstatin(1-26): The Putative Signal Peptide of Protease-Activated Receptor 1 Confers Potent Protection from Myocardial Ischemia-Reperfusion Injury
AID  - 10.1124/jpet.109.162602
DP  - 2010 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 898--905
VI  - 332
IP  - 3
4099  - http://jpet.aspetjournals.org/content/332/3/898.short
4100  - http://jpet.aspetjournals.org/content/332/3/898.full
SO  - J Pharmacol Exp Ther2010 Mar 01; 332
AB  - Parstatin, the N-terminal 41-amino-acid peptide cleaved by thrombin from the protease-activated receptor 1, protects against rat myocardial ischemia and reperfusion injury. In this study, we determined that the parstatin fragment 1-26, the putative signal peptide of protease-activated receptor 1, contains the functional domain of parstatin. We assessed a synthesized parstatin(1-26) peptide in an in vivo rat model of myocardial regional ischemia-reperfusion injury (n = 6/group). Infarct size in control rat hearts was 58 ± 1% area at risk. Parstatin(1-26) was able to reduce infarct size to 13 ± 1% (P < 0.001) and 22 ± 1% area at risk (P < 0.01) when given before or after reperfusion. The infarct-sparing effects of parstatin(1-26) were abolished by inhibition of Gi proteins (pertussis toxin), phosphoinositide 3-kinase/Akt (wortmannin), nitric-oxide synthase (NOS; NG-monomethyl-l-arginine), soluble guanylyl cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], and sarcolemmal and mitochondrial KATP channels [glibenclamide, 5-hydroxydecanoic acid, and sodium (5-(2-(5-chloro-2-methoxybenzamido)ethyl)-2-methoxyphenylsulfonyl) (methylcarbamothioyl)amide (HMR 1098)]. Parstatin(1-26) cardioprotection was also abolished by atractyloside, a mitochondrial permeability transition pore (mPTP) opener. The inhibitors and opener alone had no effect on infarct size. Furthermore, preischemic treatment with parstatin(1-26) increased Akt and endothelial NOS phosphorylation at the time of reperfusion. After a 120-min reperfusion, parstatin(1-26) increased nitric oxide levels (12 ± 0.4 to 17 ± 0.9 mmol/g tissue) and cyclic GMP levels (87 ± 21 to 395 ± 36 pmol/g tissue). Parstatin(1-26) treatment either before or after ischemia results in an extremely efficacious protection against ischemia-reperfusion injury that depends on a Gi protein-mediated pathway involving mPTP, the end effector of the preconditioning pathway. This suggests that parstatin(1-26) has a potential therapeutic role in the treatment of ischemia and reperfusion injury.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics