Faculty Collaboration Database

Tryptase/Protease-activated receptor 2 interactions induce selective mitogen-activated protein kinase signaling and collagen synthesis by cardiac fibroblasts. Hypertension 2011 Aug;58(2):264-70

Date

07/07/2011

Pubmed ID

21730297

Pubmed Central ID

PMC3437478

DOI

10.1161/HYPERTENSIONAHA.111.169417

Scopus ID

2-s2.0-80051471604 (requires institutional sign-in at Scopus site)   78 Citations

Abstract

The mast cell product, tryptase, has recently been implicated to mediate fibrosis in the hypertensive heart. Tryptase has been shown to mediate noncardiac fibroblast function via activation of protease-activated receptor 2 and subsequent activation of the mitogen-activated protein kinase pathway, including extracellular signal-regulated kinase 1/2. Therefore, we hypothesized that this pathway may be a mechanism leading to fibrosis in the hypertensive heart. Isolated adult cardiac fibroblasts were treated with tryptase, which induced activation of extracellular signal-regulated kinase 1/2 via protease-activated receptor 2. Blockade of protease activated receptor 2 with FSLLRY (10 μmol/L) and inhibition of the extracellular signal-regulated kinase pathway with PD98059 (10 μmol/L) prevented collagen synthesis in isolated cardiac fibroblasts stimulated with tryptase. In contrast, p38 mitogen-activated protein kinase and stress-activated protein/c-Jun N-terminal kinase were not activated by tryptase. Cardiac fibroblasts isolated from spontaneously hypertensive rats showed this same pattern of activation. Treatment of spontaneously hypertensive rats with FSLLRY prevented fibrosis in these animals, indicating the in vivo applicability of the cultured fibroblast findings. Also, tryptase induced a myofibroblastic phenotype indicated by elevations in α-smooth muscle actin and extra type III domain A (ED-A) fibronectin. Thus, the results from this study demonstrate the importance of tryptase for inducing a cardiac myofibroblastic phenotype, ultimately leading to the development of cardiac fibrosis. Specifically, tryptase causes cardiac fibroblasts to increase collagen synthesis via a mechanism involving activation of protease-activated receptor 2 and subsequent induction of extracellular signal-regulated kinase signaling.

Author List

McLarty JL, Meléndez GC, Brower GL, Janicki JS, Levick SP

MESH terms used to index this publication - Major topics in bold

Animals
Collagen
Fibroblasts
Male
Mitogen-Activated Protein Kinases
Myocardium
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Rats, Sprague-Dawley
Receptor, PAR-2
Signal Transduction