Mechanistic Roles of Matrilin-2 and Klotho in Modulating the Inflammatory Activity of Human Aortic Valve Cells

Abstract

Background: Calcific aortic valve disease (CAVD) is a chronic inflammatory disease. Soluble extracellular matrix (ECM) proteins can act as damage-associated molecular patterns and may induce valvular inflammation. Matrilin-2 is an ECM protein and has been found to elevate the pro-osteogenic activity in human aortic valve interstitial cells (AVICs). Klotho, an anti-aging protein, appears to have anti-inflammatory properties. The effect of matrilin-2 and Klotho on AVIC inflammatory responses remains unclear. Methods and Results: Isolated human AVICs were exposed to matrilin-2. Soluble matrilin-2 induced the production of ICAM-1, MCP-1, and IL-6. It also induced protein kinase R (PKR) activation via Toll-like receptor (TLR) 2 and 4. Pretreatment with PKR inhibitors inhibited NF-κB activation and inflammatory mediator production induced by matrilin-2. Further, recombinant Klotho suppressed PKR and NF-κB activation and markedly reduced the production of inflammatory mediators in human AVICs exposed to matrilin-2. Conclusions: This study revealed that soluble matrilin-2 upregulates AVIC inflammatory activity via activation of the TLR-PKR-NF-κB pathway and that Klotho is potent to suppress AVIC inflammatory responses to a soluble ECM protein through inhibiting PKR. These novel findings indicate that soluble matrilin-2 may accelerate the progression of CAVD by inducing valvular inflammation and that Klotho has the potential to suppress valvular inflammation.

Monocytes enhance the inflammatory response to TLR2 stimulation in aortic valve interstitial cells through paracrine up-regulation of TLR2 level

“…Our previous study revealed that neutralization of TLR2 reduces the pro-inflammatory and pro-osteogenic effects of oxLDL in human AVICs [9]. Further, we found that several ECM proteins, such as biglycan and matrilin-2, induce inflammatory and osteogenic responses in human AVICs via TLR2 and TLR4 [11,30]. The mechanistic role for TLR2 in elevating AVIC inflammatory and osteogenic activities is well established [10,30].…”

“…Moreover, we observed that human AVICs express functional Toll-like receptors (TLRs), and AVICs isolated from diseased aortic valves have higher levels of TLR2 and TLR4 [10]. More importantly, stimulation of TLRs in human AVICs not only induces inflammatory responses [7][8][9]11], but also elevates cellular osteogenic and fibrogenic activities [8][9][10][12][13][14], and the pro-inflammatory and pro-osteogenic pathways in human AVICs interact to modulate cellular inflammatory and osteogenic activities [15]. Thus, TLRs may play a mechanistic role in mediating CAVD progression [16].…”

Interleukin 38 alleviates aortic valve calcification by inhibition of NLRP3

“…Soluble matrilin-2 is a potent inducer of inflammatory and osteogenic activities in AVICs ( 14 , 19 ). We tested the hypothesis that recombinant IL-38 is capable of suppressing the inflammatory and osteogenic activities induced by ECM protein in AVICs from non-CAVD valves.…”

“…In the aortic valve, matrilin-2 can function as a damage-associated molecular pattern (DAMP) when being in a soluble form due to valvular stress or injury ( 18 ). Soluble matrilin-2 has been found to elevate AVIC inflammosteogenic (inflammatory and osteogenic) activities via activation of Toll-like receptor 2 and Toll-like receptor 4 ( 14 , 17 , 19 ). Soluble matrilin-2 can also promote the interaction of monocytes with AVICs, leading to the enhancement of inflammatory activity in AVICs ( 20 ).…”

Meta-analysis of transcriptome datasets: An alternative method to study IL-6 regulation in coronavirus disease 2019

“…Among them, ICAM1 (a well-known gene involved in viral infection and cardiovascular disease) expression has been demonstrated to be consistent with IL-6 expression in mouse macrophages [28] , [29] . Some treatments, such as Phoenix 20 and soluble matrine 2, can induce the co-expression of ICAM1 and IL-6 [30] , [31] . In human astrocytes, IL-6 can upregulate SBNO2 expression [32] .…”