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