Platelet Derived Growth Factor Alpha (PDGFRα) Induces the Activation of Cardiac Fibroblasts by Activating c-Kit

Abstract

BackgroundEnhanced platelet-derived growth factor receptor α (PDGFRα) signaling pathway activity leads to cardiac fibrosis. However, because of the pleiotropic effects of PDGFR signaling, its role in mediating the cardiac fibrotic response remains poorly understood. This study aimed to investigate the regulatory effect of c-Kit in cardiac fibroblasts activated by PDGFRα signaling.Material/MethodsA cardiac fibrosis mice model was induced using isoproterenol, and the heart tissues of mice were tested through western blotting and real-time quantitative PCR (RT-qPCR). The cardiac fibroblasts of neonatal mice were treated with PDGF-AA or transfected with small interfering RNAs (siRNAs) specific for the mouse c-Kit gene. The levels of collagen I, collagen III, and alpha-smooth muscle actin (α-SMA) were analyzed using western blotting and RT-qPCR.ResultsIn the heart of the cardiac fibrosis mice model, the activity of c-Kit was enhanced. PDGF-AA treatment accelerated the activity of c-Kit in cardiac fibroblasts. In addition, imatinib inhibited the activity of c-Kit in vivo and in vitro. Moreover, inhibition of c-Kit by siRNAs reduced the expression of α-SMA and collagens in the activated cardiac fibroblasts. Furthermore, PDGFRα directly bound c-Kit in cardiac fibroblasts and stimulated the expression of stem cell factor (SCF).ConclusionsOur data demonstrated that PDGF/PDGFRα induced the activation of cardiac fibroblasts by activating c-Kit. This study indicated that c-Kit could be used as a potential therapeutic target for treatment of cardiac fibrosis.

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

“…To determine the functional role of PDGFC in GIST, we treated T1 with recombinant PDGFC (rPDGFC) according to a previously published report [ 31 , 32 ]. PDGFRA phosphorylation was increased by rPDGFC treatment (10 ng/mL), and dose-dependently increased T1 viability (Fig.…”

“…2e and f ). KIT phosphorylation was also analyzed because PDGFC has been reported to activate KIT signaling via PDGFRA-KIT heterodimerization [ 32 ]. However, rPDGFC did not affect KIT phosphorylation in T1 cells (Fig.…”

The Microenvironment of Decellularized Extracellular Matrix from Heart Failure Myocardium Alters the Balance between Angiogenic and Fibrotic Signals from Stromal Primitive Cells

“…In particular, PDGF-AA and TGF-β2 release in CM from dECM-PH was increased compared to dECM-NH. PDGF-AA promotes fibrosis through multiple mechanisms, such as inducing proliferation, myofibroblast polarization, and collagen I synthesis in cardiac fibroblasts [48,49]. TGFβ2, instead, is involved in inducing endothelial-to-mesenchymal transition (EndMT), which is a main mechanism of cardiac fibrosis [50,51].…”

Plasma big endothelin-1 predicts new-onset atrial fibrillation after surgical septal myectomy in patients with hypertrophic cardiomyopathy

“…Mayyas, et al have demonstrated the association of endothelin-1 with platelet derived growth factor (PDGF) and connective tissue growth factor (CTGF) [4]. Both of PDGF [16] and CTGF [17] signaling pathways have been reported to be involved in the cardiac fibrosis development. Moreover, the relationship of endothelin-1 and collagen accumulation was also identified by the analysis of Masson’s trichrome stained sections [4].…”