SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts

Strande, Jennifer L.; Hsu, Anna; Su, Jidong; Fu, Xin; Gross, Garrett J.; Baker, John E.

doi:10.1007/s00395-007-0653-4

Cited by 93 publications

(71 citation statements)

References 24 publications

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“…35 Interestingly, although the PAR1-knockout mice exhibited no difference, administration of the PAR1 antagonist SCH79797 was found to reduce infarct size. 36 Likewise, PAR2 activating peptides were also found to exhibit the reverse response when administered to a mouse model of IR. 37,38 Whether the differential effects of the inhibitors versus the knockout are due to nonspecificity of the inhibitor or compensatory mechanisms related to PAR1 or PAR2 deficiency requires further elucidation.…”

Section: Ischemia Reperfusion Results In Elevated Protease Activity Tmentioning

confidence: 99%

Inflammation in Myocardial Diseases

Marchant

Boyd

Lin

et al. 2012

Circulation Research

252

165

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Inflammatory processes underlie a broad spectrum of conditions that injure the heart muscle and cause both structural and functional deficits. In this article, we address current knowledge regarding 4 common forms of myocardial inflammation: myocardial ischemia and reperfusion, sepsis, viral myocarditis, and immune rejection. Each of these pathological states has its own unique features in pathogenesis and disease evolution, but all reflect inflammatory mechanisms that are partially shared. From the point of injury to the mobilization of innate and adaptive immune responses and inflammatory amplification, the cellular and soluble mediators and mechanisms examined in this review will be discussed with a view that both beneficial and adverse consequences arise in these human conditions. (Circ Res. 2012;110:126-144.)

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Section: Ischemia Reperfusion Results In Elevated Protease Activity Tmentioning

confidence: 99%

Inflammation in Myocardial Diseases

Marchant

Boyd

Lin

et al. 2012

Circulation Research

252

165

View full text Add to dashboard Cite

show abstract

“…In contrast, a recent study found that inhibition of PAR-1 with a selective PAR-1 antagonist reduced infarct size in a rat model of cardiac I/R injury. 23 This difference could be due to the use of different models of I/R injury or off-target effects of the antagonist.…”

Section: Discussionmentioning

confidence: 99%

Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy

et al. 2007

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Background-Protease-activated receptor-1 (PAR-1) is the high-affinity receptor for the coagulation protease thrombin. It is expressed by a variety of cell types in the heart, including cardiomyocytes and cardiac fibroblasts. We have shown that tissue factor (TF) and thrombin contribute to infarct size after cardiac ischemia-reperfusion (I/R) injury. Moreover, in vitro studies have shown that PAR-1 signaling induces hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. The purpose of the present study was to investigate the role of PAR-1 in infarction, cardiac remodeling, and hypertrophy after I/R injury. In addition, we analyzed the effect of overexpression of PAR-1 on cardiomyocytes. Methods and Results-We found that PAR-1 deficiency reduced dilation of the left ventricle and reduced impairment of left ventricular function 2 weeks after I/R injury. Activation of ERK1/2 was increased in injured PAR-1 Ϫ/Ϫ mice compared with wild-type mice; however, PAR-1 deficiency did not affect infarct size. Cardiomyocyte-specific overexpression of PAR-1 in mice induced eccentric hypertrophy (increased left ventricular dimension and normal left ventricular wall thickness) and dilated cardiomyopathy. Deletion of the TF gene in cardiomyocytes reduced the eccentric hypertrophy in mice overexpressing PAR-1.Conclusions-Our results demonstrate that PAR-1 contributes to cardiac remodeling and hypertrophy. Moreover, overexpression of PAR-1 on cardiomyocytes induced eccentric hypertrophy. Inhibition of PAR-1 after myocardial infarction may represent a novel therapy to reduce hypertrophy and heart failure in humans.

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“…The pharmacology of PARs is not well developed, and inhibitors capable of blocking PAR1 function in mouse models have not been well characterized with respect to off-target effects. Nonetheless, SCH79797 has been used to probe PAR1 function in rodent models (31)(32)(33); thus, encouraged by the protection against IAV seen in Par1 -/-mice, we examined the effects of this compound on the course of IAV infection. SCH79797 inhibited PAR1-AP-induced ERK activation in mouse NIH3T3 cells ( Figure 4A), which suggests that it is capable of blocking signaling by the mouse homolog of PAR1.…”

Section: Par1 Contributes To the Pathogenesis Of Iav Infectionmentioning

confidence: 99%

PAR1 contributes to influenza A virus pathogenicity in mice

Khoufache¹,

Berri²,

Nacken³

et al. 2012

J. Clin. Invest.

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Influenza causes substantial morbidity and mortality, and highly pathogenic and drug-resistant strains are likely to emerge in the future. Protease-activated receptor 1 (PAR1) is a thrombin-activated receptor that contributes to inflammatory responses at mucosal surfaces. The role of PAR1 in pathogenesis of virus infections is unknown. Here, we demonstrate that PAR1 contributed to the deleterious inflammatory response after influenza virus infection in mice. Activating PAR1 by administering the agonist TFLLR-NH 2 decreased survival and increased lung inflammation after influenza infection. Importantly, both administration of a PAR1 antagonist and PAR1 deficiency protected mice from infection with influenza A viruses (IAVs). Treatment with the PAR1 agonist did not alter survival of mice deficient in plasminogen (PLG), which suggests that PLG permits and/or interacts with a PAR1 function in this model. PAR1 antagonists are in human trials for other indications. Our findings suggest that PAR1 antagonism might be explored as a treatment for influenza, including that caused by highly pathogenic H5N1 and oseltamivir-resistant H1N1 viruses.

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SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts

Cited by 93 publications

References 24 publications

Inflammation in Myocardial Diseases

Inflammation in Myocardial Diseases

Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy

PAR1 contributes to influenza A virus pathogenicity in mice

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