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(Circulation. 2008;117:e496.)
© 2008 American Heart Association, Inc.

Correspondence

Response to Letter Regarding Article, "Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy"

Rafal Pawlinski, PhD; Michael Tencati, BS

The Scripps Research Institute, Department of Immunology, La Jolla, Calif

Craig R. Hampton, MD; Denise Spring, PhD; Timothy H. Pohlman, MD; Edward D. Verrier, MD

University of Washington, Division of Cardiothoracic Surgery, Seattle, Wash

Tetsuro Shishido, MD, PhD; Tara A. Bullard, PhD; Liam M. Casey, MD; Jun-ichi Abe, MD, PhD; Burns C. Blaxall, PhD

University of Rochester Medical Center, Cardiovascular Research Institute, Rochester, NY

Patricia Andrade-Gordon, PhD

Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pa

Matthias Kotzsch, MD; Thomas Luther, MD

Institute of Pathology, Technical University of Dresden, Dresden, Germany

Nigel Mackman, PhD

University of North Carolina at Chapel Hill, Department of Medicine, Chapel Hill, NC

We recently reported that a genetic absence of protease activated receptor-1 (PAR-1) improved cardiac function by reducing remodeling but did not affect infarct size in an in vivo mouse model of cardiac ischemia-reperfusion injury.¹ In contrast, Strande and colleagues² found that administration of the non–peptide PAR-1 antagonist SCH 79797 to rats significantly reduced infarct size in a similar cardiac ischemia-reperfusion model.

One can debate the pros and cons of pharmacological versus genetic approaches at length. Obviously, the best case scenario is that the results of both approaches match. In the case of the role of PAR-1 in infarct size, however, opposite results were observed. A concern with all pharmacological inhibitors is specificity. SCH 79797 was originally developed as an inhibitor of human PAR-1 by Schering-Plough; however, further development was halted by the company.³ Another anti-human PAR-1 compound developed by the same company called SCH 530348 is currently undergoing evaluation in the TRANSCENDENCE (Thrombin Receptor Antagonist for Clinical Event Reduction Over Standard Concomitant Therapies) phase II clinical trial.⁴ This is a multicenter randomized trial investigating the safety of various doses of SCH 530348 when used in the nonemergent percutaneous coronary intervention setting.⁴ Unfortunately, in most cases, researchers do not have access to pharmaceutical drugs that are being tested in clinical trials and we have to make do with discarded drugs. We suggested in our article¹ that the difference between our data with PAR-1^–/– mice and the results with SCH 79797 made be due to off-target effects of the compound that may occur in vivo. Importantly, a recent study⁵ demonstrated that SCH 79797 interfered with the growth of several human and mouse cell lines and that the antiproliferative activity of SCH 79797 was found to be independent of PAR-1.

We are continuing to explore the role of PAR-1 in cardiac ischemia-reperfusion injury and agree that the next step is to examine the effect of inhibition of PAR-1 in wild-type mice. However, we believe that the best approach is to compare the effect of more than one mouse PAR-1 inhibitor, such as a small molecule inhibitor and an anti-mouse PAR-1 antibody. Furthermore, these inhibitors must be shown to inhibit mouse PAR-1 signaling in cultured cells before testing in the cardiac ischemia-reperfusion injury model. In addition, experiments with the various PAR-1 inhibitors in both wild-type and PAR-1^–/– mice would provide evidence of their specificity.

	Acknowledgments

 
Source of Funding

This work was supported by grant HL084087 from the National Institutes of Health.

Disclosures

None.

	References

Top References

 

1. Pawlinski R, Tencati M, Hampton C, Shishido T, Bullard TA, Casey L, Andrade-Gordon P, Kotzsch M, Spring D, Luther T, Abe J, Pohlman T, Verrier E, Blaxall B, Mackman N. Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation. 2007; 116: 2298–2306.[Abstract/Free Full Text]
   
2. Strande JL, Hsu A, Su J, Fu X, Gross GJ, Baker JE. SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts. Basic Res Cardiol. 2007; 102: 350–358.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Ahn HS, Foster C, Boykow G, Stamford A, Manna M, Graziano M. Inhibitionof cellular activation of thrombin by N3-cyclopropyl-7-[4-(1-methly)phenly]methyl]-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (SCH 79797), a nonpeptide thrombin receptor antogonist. Biochem Phamacol. 2000; 60: 1425–1434.[CrossRef][Medline] [Order article via Infotrieve]
   
4. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res. 2007; 100: 1261–1275.[Abstract/Free Full Text]
   
5. Di Serio C, Pellerito S, Duarte M, Massi D, Naldini A, Cirino G, Prudovsky I, Santucci M, Geppetti P, Marchionni N, Masotti G, Tarantini F. Protease-activated receptor 1-selective antagonist SCH79797 inhibits cell proliferation and apoptosis by a protease-activated receptor 1-independent mechanism. Basic Clin Pharmacol Toxicol. 2007; 101: 63–69.[CrossRef][Medline] [Order article via Infotrieve]
   

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