Tryptase/Protease-Activated Receptor 2 Interactions Induce Selective Mitogen-Activated Protein Kinase Signaling and Collagen Synthesis by Cardiac Fibroblasts

Abstract

The mast cell product, tryptase, has recently been implicated in fibrosis in the hypertensive heart. Tryptase has been shown to mediate non-cardiac fibroblast function via activation of protease activated receptor-2 and subsequent activation of the mitogen-activated protein kinase pathway, including extracellular signal-regulated kinase1/2. 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 kinase1/2 via protease activated receptor-2. Blockade of protease activated receptor-2 with FSLLRY (10 μM) and inhibition of the extracellular signal-regulated kinase pathway with PD98059 (10 μM) prevented collagen synthesis in isolated cardiac fibroblasts stimulated with tryptase. 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 and 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 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 through the activation of the extracellular signal-regulated kinase pathway. 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.

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

“…110 Tryptase promoted cardiac fibroblast proliferation and collagen synthesis via activation of proteaseactivated receptor 2. 114 Administration of protease-activated receptor 2 antagonist prevented cardiac fibrosis in spontaneously hypertensive rats. 114 These findings suggest a causal relationship between cardiac mast cells and the pathological process of cardiac hypertrophy and fibrosis (Figure ; Table).…”

A Brief Exposure to Tryptase or Thrombin Potentiates Fibrocyte Differentiation in the Presence of Serum or Serum Amyloid P

“…Intratracheal administration of tryptase causes inflammation, and inhibition of tryptase attenuates this inflammation (43–46). Inhibition of PAR-2 receptors attenuates collagen deposition in a heart disease model (47). …”

Mast Cell Tryptase Induces Microglia Activation via Protease-activated Receptor 2 Signaling

“…The role of PAR-2, which is widely distributed throughout the nervous system, has been principally investigated in the peripheral nervous system, where it is known to play major roles in injury, inflammation, neuronal signaling, and nociception [9,10]. McLarty reported that tryptase/ PAR 2 interactions induce selective mitogen-activated protein kinase signaling and collagen synthesis by cardiac fibroblasts [11]. PAR-2 is also known to be expressed on neurons, astrocytes and microglia in CNS, and several studies have implicated that it is involved in the pathogenesis of ischemia and neurodegeneration [12,13].…”