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?-adrenergic receptor stimulation transactivates protease-activated receptor 1 via matrix metalloproteinase 13 in cardiac cells.

ABSTRACT: Chronic ?-adrenergic receptor (?-AR) overstimulation, a hallmark of heart failure, is associated with increased cardiac expression of matrix metalloproteinases (MMPs). MMP-1 has been shown to cleave and activate the protease-activated receptor 1 (PAR1) in noncardiac cells. In the present study, we hypothesized that ?-AR stimulation would result in MMP-dependent PAR1 transactivation in cardiac cells.?-AR stimulation of neonatal rat ventricular myocytes (NRVMs) or cardiac fibroblasts with isoproterenol transduced with an alkaline phosphatase-tagged PAR1 elicited a significant increase in alkaline phosphatase-PAR1 cleavage. This isoproterenol-dependent cleavage was significantly reduced by the broad-spectrum MMP inhibitor GM6001. Importantly, specific MMP-13 inhibitors also decreased alkaline phosphatase-PAR1 cleavage in isoproterenol-stimulated NRVMs, as well as in NRVMs stimulated with conditioned medium from isoproterenol-stimulated cardiac fibroblasts. Moreover, we found that recombinant MMP-13 stimulation cleaved alkaline phosphatase-PAR1 in NRVMs at DPRS(42)?(43)FLLRN. This also led to the activation of the ERK1/2 pathway through G?q in NRVMs and via the G?q/ErbB receptor pathways in cardiac fibroblasts. MMP-13 elicited similar levels of ERK1/2 activation but lower levels of generation of inositol phosphates in comparison to thrombin. Finally, we demonstrated that either PAR1 genetic ablation or pharmacological inhibition of MMP-13 prevented isoproterenol-dependent cardiac dysfunction in mice.In this study, we demonstrate that ?-AR stimulation leads to MMP-13 transactivation of PAR1 in both cardiac fibroblasts and cardiomyocytes and that this likely contributes to pathological activation of G?q and ErbB receptor-dependent pathways in the heart. We propose that this mechanism may underlie the development of ?-AR overstimulation-dependent cardiac dysfunction.

SUBMITTER: Jaffre F

PROVIDER: S-EPMC3386307 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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β-adrenergic receptor stimulation transactivates protease-activated receptor 1 via matrix metalloproteinase 13 in cardiac cells.

Jaffré Fabrice F Friedman Alan E AE Hu Zhaoyang Z Mackman Nigel N Blaxall Burns C BC

Circulation 20120518 24

<h4>Background</h4>Chronic β-adrenergic receptor (β-AR) overstimulation, a hallmark of heart failure, is associated with increased cardiac expression of matrix metalloproteinases (MMPs). MMP-1 has been shown to cleave and activate the protease-activated receptor 1 (PAR1) in noncardiac cells. In the present study, we hypothesized that β-AR stimulation would result in MMP-dependent PAR1 transactivation in cardiac cells.<h4>Methods and results</h4>β-AR stimulation of neonatal rat ventricular myocyt ...[more]

PMID: 22610965

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Project description:BackgroundFibrostenotic disease is a common complication in Crohn's disease (CD) patients hallmarked by transmural extracellular matrix (ECM) accumulation in the intestinal wall. The prevention and medical therapy of fibrostenotic CD is an unmet high clinical need. Although targeting IL36R signaling is a promising therapy option, downstream mediators of IL36 during inflammation and fibrosis have been incompletely understood. Candidate molecules include matrix metalloproteinases which mediate ECM turnover and are thereby potential targets for anti-fibrotic treatment. Here, we have focused on understanding the role of MMP13 during intestinal fibrosis.MethodsWe performed bulk RNA sequencing of paired colon biopsies taken from non-stenotic and stenotic areas of patients with CD. Corresponding tissue samples from healthy controls and CD patients with stenosis were used for immunofluorescent (IF) staining. MMP13 gene expression was analyzed in cDNA of intestinal biopsies from healthy controls and in subpopulations of patients with CD in the IBDome cohort. In addition, gene regulation on RNA and protein level was studied in colon tissue and primary intestinal fibroblasts from mice upon IL36R activation or blockade. Finally, in vivo studies were performed with MMP13 deficient mice and littermate controls in an experimental model of intestinal fibrosis. Ex vivo tissue analysis included Masson's Trichrome and Sirius Red staining as well as evaluation of immune cells, fibroblasts and collagen VI by IF analysis.ResultsBulk RNA sequencing revealed high upregulation of MMP13 in colon biopsies from stenotic areas, as compared to non-stenotic regions of patients with CD. IF analysis confirmed higher levels of MMP13 in stenotic tissue sections of CD patients and demonstrated αSMA+ and Pdpn+ fibroblasts as a major source. Mechanistic experiments demonstrated that MMP13 expression was regulated by IL36R signaling. Finally, MMP13 deficient mice, as compared to littermate controls, developed less fibrosis in the chronic DSS model and showed reduced numbers of αSMA+ fibroblasts. These findings are consistent with a model suggesting a molecular axis involving IL36R activation in gut resident fibroblasts and MMP13 expression during the pathogenesis of intestinal fibrosis.ConclusionTargeting IL36R-inducible MMP13 could evolve as a promising approach to interfere with the development and progression of intestinal fibrosis.

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?-adrenergic receptor stimulation transactivates protease-activated receptor 1 via matrix metalloproteinase 13 in cardiac cells.

Publications

β-adrenergic receptor stimulation transactivates protease-activated receptor 1 via matrix metalloproteinase 13 in cardiac cells.

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