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Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 20, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp122
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Parstatin: a cryptic peptide involved in cardioprotection after ischemia and reperfusion injury

Jennifer L. Strande1,*, Michael E. Widlansky1, Nikos E. Tsopanoglou2, Jidong Su3, JingLi Wang1, Anna Hsu4, Kasi V. Routhu1 and John E. Baker3

1 Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI
2 Department of Pharmacology, Medical School, University of Patras, Rio-Patras Greece
3 Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, WI
4 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI

* Address for correspondence: Jennifer L. Strande, M.D., Ph.D., Division of Cardiovascular Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, Telephone: 414-456-8895, Fax: 414-453-9700, E-mail: jstrande{at}mcw.edu

Aims: Thrombin activates protease activated receptor (PAR) 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 ischemia-reperfusion injury.

Methods and Results: We assessed the protective role of Parstatin in an in vivo and in vitro rat model of myocardial ischemia-reperfusion injury. Parstatin treatment before, during and after ischemia decreased infarct size by 26, 23, and 18%, respectively, in an in vivo model of ischemia-reperfusion injury. Parstatin treatment immediately before ischemia 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 KATP 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.

Conclusion: A single treatment of Parstatin administered prior to ischemia confers immediate cardioprotection by recruiting the Gi protein activation pathway including p38 MAPK, ERK1/2, NOS, and KATP channels. Parstatin exerts effects on both cardiomyocytes and the coronary circulation to induce cardioprotection. This suggests a potential therapeutic role of Parstatin in the treatment of cardiac injury resulting from ischemia and reperfusion.

KEYWORDS Cryptic peptide; Cardioprotection; Ischemia; Reperfusion Injury; Vasodilation

Time for primary review: 21 Days


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