Pro-inflammatory mediators released by activated monocytes promote aortic valve fibrocalcific activity

Peijian Zhang,Zichao Luo,Xianzhong Meng,Lihua Ao,Erlinda The,Yufeng Zhai,David A Fullerton,Qingzhou Yao,Dingli Xu

doi:10.1186/s10020-022-00433-4

Abstract

BackgroundCalcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. Valvular fibrocalcification is a characteristic pathological change. In diseased valves, monocyte accumulation is evident, and aortic valve interstitial cells (AVICs) display greater fibrogenic and osteogenic activities. However, the impact of activated monocytes on valular fibrocalcification remains unclear. We tested the hypothesis that pro-inflammatory mediators from activated monocytes elevate AVIC fibrogenic and osteogenic activities.Methods and resultsPicro-sirius red staining and Alizarin red staining revealed collagen and calcium depositions in cultured human AVICs exposed to conditioned media derived from Pam3CSK4-stimulated monocytes (Pam3 CM). Pam3 CM up-regulated alkaline phosphatase (ALP), an osteogenic biomarker, and extracellular matrix proteins collagen I and matrix metalloproteinase-2 (MMP-2). ELISA analysis identified high levels of RANTES and TNF-α in Pam3 CM. Neutralizing RANTES in the Pam3 CM reduced its effect on collagen I and MMP-2 production in AVICs while neutralizing TNF-α attenuated the effect on AVIC ALP production. In addition, Pam3 CM induced NF-κB and JNK activation. While JNK mediated the effect of Pam3 CM on collagen I and MMP-2 production, NF-κB was critical for the effect of Pam3 CM on ALP production in AVICs.ConclusionsThis study demonstrates that activated monocytes elevate the fibrogenic and osteogenic activities in human AVICs through a paracrine mechanism. TNF-α and RANTES mediate the pro-fibrogenic effect of activated monocytes on AVICs through activation of JNK, and TNF-α also activates NF-κB to elevate AVIC osteogenic activity. The results suggest that infiltrated monocytes elevate AVIC fibrocalcific activity to promote CAVD progression.

Highlights

Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly
This study demonstrates that activated monocytes elevate the fibrogenic and osteogenic activities in human Aortic valve interstitial cell (AVIC) through a paracrine mechanism
Tumor necrosis factor-α (TNF-α) and RANTES mediate the pro-fibrogenic effect of activated monocytes on AVICs through activation of Jun N-terminal kinase (JNK), and TNF-α activates Nuclear factor kappa-B (NF-κB) to elevate AVIC osteogenic activity

Summary

Introduction

Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. Monocyte accumulation is evident, and aortic valve interstitial cells (AVICs) display greater fibrogenic and osteogenic activities. Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly (Yutzey et al 2014; Otto and Prendergast 2014). This disease is a major health care issue since it causes significant morbidity. Valvular fibrosis and calcification are characteristic of CAVD pathobiology (Miller et al 2011; Weiss et al 2013) In this regard, histopathologic examinations of aortic valves from CAVD patients demonstrated that valvular tissue thickens with excesses of fibrotic materials and calcified nodules (Lindman et al 2016). Understanding the cellular and molecular mechanisms underlying valvular fibrocalcification would enable the exploration of pharmacological interventions for prevention of CAVD progression

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