Faculty Collaboration Database

Parstatin: a cryptic peptide involved in cardioprotection after ischaemia and reperfusion injury. Cardiovasc Res 2009 Jul 15;83(2):325-34

Date

04/22/2009

Pubmed ID

19380418

Pubmed Central ID

PMC2701720

DOI

10.1093/cvr/cvp122

Scopus ID

2-s2.0-67650236404 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

AIMS: 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.

METHODS AND 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.

CONCLUSION: 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.

Author List

Strande JL, Widlansky ME, Tsopanoglou NE, Su J, Wang J, Hsu A, Routhu KV, Baker JE

Authors

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin
Michael E. Widlansky MD Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Cardiotonic Agents
Coronary Circulation
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors
Extracellular Signal-Regulated MAP Kinases
GTP-Binding Protein alpha Subunits, Gi-Go
Guanylate Cyclase
Heart Rate
KATP Channels
Male
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
Nitric Oxide Synthase Type III
Peptide Fragments
Potassium Channel Blockers
Rats
Rats, Sprague-Dawley
Receptor, PAR-1
Receptors, Cytoplasmic and Nuclear
Signal Transduction
Soluble Guanylyl Cyclase
Time Factors
Vasodilation
Ventricular Function, Left
p38 Mitogen-Activated Protein Kinases