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.
Highlights
Calcific aortic valve disease (CAVD) is one of the most common heart valve diseases in the elderly [1]
Suppressed the expression of ICAM-1 (Figure 3D,E), and the production of MCP-1 and IL-6 production (Figure 3F,G). These findings reveal that protein kinase R (PKR) is upstream of NF-κB and that the PKR-NF-κB signaling pathway mediates the inflammatory responses to soluble matrilin-2 in human aortic valve interstitial cells (AVICs)
Because TLR2 and TLR4 play an important role in mediating pro-inflammatory and pro-osteogenic responses, we examined whether TLR2 and TLR4 mediate PKR activation induced by matrilin-2 in human AVICs
Summary
Calcific aortic valve disease (CAVD) is one of the most common heart valve diseases in the elderly [1]. There is no effective pharmacotherapy treatment for CAVD [3]; the only viable treatment option is surgical or interventional valve replacement. These interventions are costly and have limitations due to complications of anticoagulation therapy and the short lifespan of prosthetic valves [4]. Recent evidence suggests that CAVD is the result of a chronic inflammatory process that promotes aortic valve fibrosis and calcification [6,7]. Calcific aortic valve disease (CAVD) is a chronic inflammatory disease. Matrilin-2 is an ECM protein and has been found to elevate the pro-osteogenic activity in human aortic valve interstitial cells (AVICs). Methods and Results: Isolated human AVICs were exposed to matrilin-2
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