Cathelicidin Modulates Vascular Smooth Muscle Cell Phenotypic Switching through ROS/IL-6 Pathway.

Xiaoliang Dong,Di Wu,Li-Long Pan,Jia Sun,Xiaohua Pan,Yihan Zhang,Lingling Jia

doi:10.3390/antiox9060491

Abstract

Vascular smooth muscle cells (VSMC) are stromal cells of the blood vessels and their differentiation is thought to be essential during atherosclerosis. Cathelicidin-related antimicrobial peptides (CRAMP) are suggested to play a role in the development of atherosclerosis. Even so, the relationship of CRAMP and VSMC remains unclear. The present study was to determine whether CRAMP regulates VSMC phenotypic transformation and underlying mechanisms. We demonstrated that CRAMP could reverse platelet-derived growth factor-BB (PDGF-BB)-induced VSMC phenotypic transformation, evidencing by increasing α-smooth muscle actin (α-SMA), smooth muscle 22α (SM22α) and decreasing of proliferation and migration. Further studies showed that CRAMP inhibited nuclear factor κB (NF-κB)-induced autocrine of interleukin-6 (IL-6), which further activated of janus kinase 2 (JAK2)/signal transducer and activator 3 (STAT3). Meanwhile, our data showed that CRAMP can significantly inhibit PDGF-BB enhanced intracellular reactive oxygen species (ROS) level which further affected the NF-κB signaling pathway, indicating that CRAMP can regulate the phenotypic transformation of VSMC by regulating oxidative stress. These results indicated that CRAMP regulated the differentiation of VSMC by inhibiting ROS-mediated IL-6 autocrine, suggesting that targeting CRAMP is a potential avenue for regulating the differentiation of VSMC and treatment of atherosclerosis.

Highlights

Cardiovascular disease, the world’s leading cause of death, claiming an estimated 17.9 million lives each year, is a group of heart and vascular diseases such as atherosclerosis [1]
We found that Cathelicidin-related antimicrobial peptides (CRAMP) alleviated platelet-derived growth factor-BB (PDGF-BB)-induced proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMC) through modulating reactive oxygen species (ROS)/nuclear factor κB (NF-κB), which was dependent on IL-6 autocrine
These results suggested that CRAMP could inhibit PDGF-BB-induced VSMC phenotypic transformation

Summary

Introduction

Cardiovascular disease, the world’s leading cause of death, claiming an estimated 17.9 million lives each year, is a group of heart and vascular diseases such as atherosclerosis [1]. In the study of the development of atherosclerosis, more and more emphasis has been placed on the phenotypic transformation of vascular smooth muscle cells (VSMC) [2]. VSMC phenotypic modulation from a contractile to a synthetic phenotype in vessel walls, triggered by harmful microenvironmental stimuli and followed by VSMC migration and proliferation, is critical for the development of proliferative vascular disease [3,4,5]. Phenotypic modulation of VSMC from a quiescent and contractile type to synthetic phenotype is an important step in the development of several pathophysiological processes such as atherosclerosis, restenosis and vascular remodeling [6,7]. Imbalanced VSMC plasticity results in maladaptive phenotype alterations that lead to progression of a variety of VSMC-driven vascular diseases [8]. Regulating VSMC phenotype transformation may be a means of treating cardiovascular disease

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