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(Circulation. 2008;117:e495.)
© 2008 American Heart Association, Inc.

Correspondence

Letter by Strande Regarding Article "Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy"

Jennifer L. Strande, MD, PhD

Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, Wis

To the Editor:

I read the article by Pawlinski et al¹ with great interest. The authors showed that protease-activated receptor-1 (PAR-1)–deficient mice had preservation of left ventricular size and function after myocardial ischemia and reperfusion (IR) injury when compared with wild-type littermates. Conversely, PAR-1–deficient mice did not have a decreased myocardial infarct size after IR injury. The authors then went on to show that mice selectively overexpressing PAR-1 in cardiomyocytes developed left ventricular dilatation and dysfunction when compared with wild-type littermates. This is very exciting data with great translational potential, especially when considering the ongoing clinical development of a PAR-1 antagonist for other indications (ClinicalTrials.gov Identifier: NCT00526474).

My concern for the translational potential of their study regards their observation that PAR-1 deficiency in mice did not protect against acute myocardial IR injury. We have previously shown that a competitive inhibitor of PAR-1 (SCH 79797) protects the rat heart against acute IR injury.² The authors¹ explain this discrepancy by suggesting the PAR-1 antagonist may have off-target effects that are responsible for the decreased infarct size after IR. In our study,² we confirmed PAR-1 selectivity of SCH 79797 by showing that a PAR-1–activating peptide completely abolished the cardioprotective effects of SCH 79797. The difference in acute cardioprotection between the 2 studies would suggest that the PAR-1–deficient heart does not mimic the same pathological response as a normal heart treated with a PAR-1 antagonist. This suggests that PAR-1 antagonists may not protect against cardiomyopathy.

An alternate explanation for their findings might be that another PAR, such as PAR-4, is compensating for the PAR-1 deficiency. For instance, only 50% of PAR-1–deficient embryos survive and develop normally, which suggests that another receptor is compensating for the absence of PAR-1. Both PAR-1 and PAR-4 are expressed in the myocardium and activated by thrombin. Therefore, PAR-4 will still be activated by thrombin during IR when PAR-1 is absent. We have recently shown³ that PAR-4 is also implicated in IR injury, as the inhibition of PAR-4 by 2 structurally different antagonists decreased myocardial infarct size associated with IR. It would be interesting to know if hirudin treatment of PAR-1–deficient mice could decrease infarct size from myocardial IR injury; if it did, then this would incriminate PAR-4 as the mediator of IR injury in this model.

Most likely, PAR-1 deficiency mimics the effects of PAR-1 antagonists only when PAR-4 is not able to compensate. For example, in the kidney, which normally lacks PAR-4, both PAR-1 deficiency and SCH 79797 protect against renal IR injury.^4,5 Currently, no evidence exists showing that PAR-4 is involved in the pathogenesis of heart failure or cardiomyocyte hypertrophy. This suggestion correlates with the elegant studies provided by Pawloski et al.¹ Therefore, PAR-1 antagonists have great potential to be part of the regimen for the treatment of heart failure.

	Acknowledgments

 
Disclosures

None.

	References

Top References

 

1. Pawlinski R, Tencati M, Hampton CR, Shishido T, Bullard TA, Casey LM, Andrade-Gordon P, Kotzsch M, Spring D, Luther T, Abe J-i, Pohlman TH, Verrier ED, Blaxall BC, 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. Strande JL, Hsu A, Su J, Fu X, Gross GJ, Baker JE. Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signaling. J Pharmacol Exp Ther. 2008; 324: 1045–1054.[Abstract/Free Full Text]
   
4. Erlich J, Kennedy S, Peake P, Charlesworth J. The protease activated receptor 1 inhibitor SCH79797 protects against renal ischaemia reperfusion injury. Nephrology. 2007; 12 (supplement): A1065. Abstract.
   
5. Sevastos J, Kennedy SE, Davis DR, Sam M, Peake PW, Charlesworth JA, Mackman N, Erlich JH. Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood. 2007; 109: 577–583.[Abstract/Free Full Text]
   

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Strande, J. L. PubMed PubMed Citation Articles by Strande, J. L. Pubmed/NCBI databases Medline Plus Health Information Heart Attack Related Collections Other heart failure Animal models of human disease Receptor pharmacology