c-Kit modifies the inflammatory status of smooth muscle cells

Abstract

Backgroundc-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis.MethodsHigh-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (KitW/W–v) and control (Kit+/+) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations.ResultsThe microarray analysis revealed elevated NF-κB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-κB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-κB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-κB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-κB activity in SMC in a TGFβ-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner.DiscussionOur study suggests a novel mechanism by which c-Kit suppresses NF-κB regulated pathways in SMC to prevent their pro-inflammatory transformation.

M2 macrophage-derived exosomes promote the c-KIT phenotype of vascular smooth muscle cells during vascular tissue repair after intravascular stent implantation

“…We provide evidence that exogenous M2Es induce vascular repair through VSMC expressing c-KIT. It is possible that c-KIT suppresses nuclear factor kappa-B (NF-κB)-regulated pathways in VSMCs to prevent their pro-inflammatory transformation 9 , 12 .…”

“…On the other hand, VSMCs may exhibit stem cell properties, including the expression of stem cell markers (such as c-KIT) 9 , softness 10 , and high proliferation in response to inflammation or other microenvironmental factors in the vascular injury site. Stem cell marker expression by VSMCs occurs in the early injury phases, which probably plays a major role in vascular remodeling 11 , 12 .…”

c-Kit suppresses atherosclerosis in hyperlipidemic mice

“…5, G and H) and total cholesterol levels compared with c-Kit rescued cells and those from controls (P Ͻ 0.01). These results prompted us to search our tran-scriptomic data on Kit Mut and Kit WT SMCs for differentially expressed genes that code for scavenger receptors and lipid hemostasis proteins (43). We discovered that the ATPbinding cassette transporter G1 (ABCG1) gene was signif- Protein expression in C was normalized using ␤-actin levels and then standardized against Kit WT .…”

“…Knockdown of c-Kit decreased expression of myocardin-regulated contractile genes in primary SMC cultures (15), suggesting a key role for this RTK in promoting full SMC differentiation. We have recently revealed the importance of c-Kit in the preservation of SMC's antiinflammatory signaling when challenged with oxidized phospholipids (43). In light of this in vitro evidence, the influence of c-Kit signaling on vascular disease deserves further attention.…”

Identification of Epigenetic Mechanisms Involved in the Anti-Asthmatic Effects of Descurainia sophia Seed Extract Based on a Multi-Omics Approach

“…Furthermore, several studies have reported that Vegfa levels are increased in tissues and biological samples from asthma patients [ 40 , 41 , 42 ]. Kit , which was regulated in a “down/up” fashion, due to its hyper/hypo methylation pattern, is related to the NF-κB signaling pathway, which regulates pro-inflammatory mediators [ 43 ], and may help to maintain alveolar structure [ 44 ]. These results indicate that methylation changes of two hub genes play important roles in regulating the anti-inflammatory effect.…”