Protease-Activated Receptor 1 Inhibition by SCH79797 Attenuates Left Ventricular Remodeling and Profibrotic Activities of Cardiac Fibroblasts

Sonin, Dmitry; Wakatsuki, Toshiyuki; Routhu, Kasi V.; Harmann, Leanne; Petersen, Matthew; Meyer, Jennifer A.; Strande, Jennifer L.

doi:10.1177/1074248413485434

Cited by 60 publications

(40 citation statements)

References 40 publications

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“…Additionally, PAR‐1‐dependent TGF‐β production by TECs, as observed in our in vitro experiments and as described before for HK2 cells, may further induce fibroblast proliferation and activation thereby further enhancing renal fibrosis. This latter notion is supported by recent findings that PAR‐1 stimulation of cardiac fibroblasts also leads to TGF‐β production with subsequent myofibroblast accumulation …”

Section: Discussionsupporting

confidence: 63%

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Waasdorp

Rooij

Florquin

et al. 2018

J Cellular Molecular Medi

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End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease‐activated receptor (PAR)‐1, which recently emerged as an inducer of epithelial‐to‐mesenchymal transition (EMT), aggravates renal fibrosis. We show that PAR‐1 activation on TECs reduces the expression of epithelial markers and simultaneously induces mesenchymal marker expression reminiscent of EMT. We next show that kidney damage was reduced in PAR‐1‐deficient mice during unilateral ureter obstruction (UUO) and that PAR‐1‐deficient mice develop a diminished fibrotic response. Importantly, however, we did hardly observe any signs of mesenchymal transition in both wild‐type and PAR‐1‐deficient mice suggesting that diminished fibrosis in PAR‐1‐deficient mice is not due to reduced EMT. Instead, the accumulation of macrophages and fibroblasts was significantly reduced in PAR‐1‐deficient animals which were accompanied by diminished production of MCP‐1 and TGF‐β. Overall, we thus show that PAR‐1 drives EMT of TECs in vitro and aggravates UUO‐induced renal fibrosis although this is likely due to PAR‐1‐dependent pro‐fibrotic cytokine production rather than EMT.

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Section: Discussionsupporting

confidence: 63%

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Waasdorp

Rooij

Florquin

et al. 2018

J Cellular Molecular Medi

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“…Sham control mice underwent a similar procedure in which a suture was passed around the aorta but removed without tying (24). Blood flow velocity between the innominate and left common carotid artery was measured by Doppler (Indus Instruments, Houston, TX) before and after surgery.…”

Section: Methodsmentioning

confidence: 99%

“…TGF-b, responsible for cellular proliferation and differentiation, and procollagen secretion resulting from thrombin induced PAR-1 and ERK1/2 signaling and down regulation of matrix metalloproteinase (MMP, involved in the breakdown of extracellular matrix) demonstrates the importance of thrombin in this disease process (24). Prevention of thrombin associated stiffening and contraction of cardiac fibroblast tissue through the Inhibition of PAR-1 was shown to be effective.…”

Section: Introductionmentioning

confidence: 99%

Direct thrombin inhibition with dabigatran attenuates pressure overload-induced cardiac fibrosis and dysfunction in mice

Dong

Müeller²,

Yang³

et al. 2017

Thrombosis Research

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Introduction The multifunctional serine protease thrombin exerts proinflammatory and profibrotic cellular effects that may contribute to cardiac remodeling. This study was designed to investigate whether direct thrombin inhibition with dabigatran attenuates myocardial injury in the setting of pressure overload-induced heart failure. Material and Methods Transverse aortic constriction (TAC) surgery was performed on C57Bl/6J male mice to elicit cardiac hypertrophy. TAC, or sham, mice were randomly assigned to receive chow supplemented with the oral anticoagulant, dabigatran etexilate, or placebo. Results Dabigatran did not affect cardiac hypertrophy, as measured by heart weight-to-body weight or the heart weight-to-tibia length, although a non-significant reduction in myocardial hypertrophic markers (ANP, BNP and MHC) occurred. Dabigatran reduced perivascular fibrosis by 25%, interstitial fibrosis by 54%, and the expression of myocardial fibrosis markers collagen I & III, MMP9, SMA, and PAR-1. These changes were associated with significant improvement in both coronary flow reserve and global left ventricular function. In cultured cardiac fibroblasts, dabigatran decreased thrombin and PAR-1-mediated collagen deposition by 30% and 37%, respectively. Conclusions Dabigatran attenuates cardiac fibrosis in the setting of pressure overload and improves coronary flow reserve and global cardiac function possibly by inhibiting thrombin activity and down-regulating PAR-1 expression in the absence of an effect on cardiomyocyte hypertrophy.

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“…Inhibition or deletion of PAR1 prevents fibrosis in several cell culture-based and animal models of fibrosis including liver [86], heart [87], and lung [88]. Colitis induced in an experimental model was markedly decreased in PAR1 knockout mice or in mice exposed to the PAR1 antagonist RW-56110 compared with control and expression of PAR1 was upregulated in intestinal biopsies from patients with colitis [89].…”

Section: Indications For Par1 Modulationmentioning

confidence: 99%

Targeting PAR1: Now What?

Flaumenhaft

Ceunynck

2017

Trends in Pharmacological Sciences

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Protease-activated receptors (PARs) are a ubiquitously expressed class of GPCRs that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market. New understanding of mechanisms of PAR1 function, discovery of improved strategies for modifying PAR1 function, and identification of novel indications for PAR1 modulators have provided new opportunities for therapies targeting PAR1. This review will critically evaluate prospects for the next generation of PAR1-targeted therapeutics.

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Protease-Activated Receptor 1 Inhibition by SCH79797 Attenuates Left Ventricular Remodeling and Profibrotic Activities of Cardiac Fibroblasts

Cited by 60 publications

References 40 publications

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Direct thrombin inhibition with dabigatran attenuates pressure overload-induced cardiac fibrosis and dysfunction in mice

Targeting PAR1: Now What?

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