Abstract
Calcific aortic valve disease (CAVD) is prevalent in the elderly. The inflammatory response of aortic valve interstitial cells (AVICs) contributes to the mechanism of CAVD progression. Our previous work demonstrated that the innate immunity mediated by Toll-like receptors (TLRs) in human AVICs up-regulates the production of inflammatory mediators and pro-osteogenic activity and that human AVICs express anti-aging protein Klotho, and Klotho deficiency is responsible for the enhanced osteogenic activity in diseased AVICs. Autophagy plays an important role in modulating cellular inflammatory response. Currently, the effect of Klotho on AVIC autophagy function and inflammatory response is unknown. We hypothesis that Klotho suppresses AVIC inflammatory response through maintaining cellular autophagy activity. Methods: Levels of autophagy proteins (LC3-I, and LC3-II), Klotho and ICAM-1 were determined in AVICs of normal valves from young (25.3±2.7 years) and older (61.5±4.3 years) donors by immunoblotting. Autophagy modulators (rapamycin, 2.0 μM; Autophinib, 100 nM and Bafilomysin A1, 10 nM) and recombinant Klotho (5.0 μg/ml) were applied to AVICs to assess their impact on inflammatory responses. Results: AVICs from older donors have lower levels of Klotho and autophagy activity, but produce higher levels of ICAM-1. TLR4 stimulation in AVICs from young donors reduces cellular levels of Klotho and autophagy activity, and increases ICAM-1 production. Further, recombinant Klotho enhances autophagy activity in AVICs from older donors through induction of PTEN and inhibition the Akt-mToR-p70S6K pathway, and it suppresses the inflammatory response in unstimulated AVICs from older donors and stimulated cells from young donors. Down-regulation of autophagy enhances, while up-regulation of autophagy reduces, the inflammatory response in AVICs. Conclusions: Autophagy plays an important role in suppression of human AVIC inflammatory response. Klotho deficiency in AVICs associated with aging exaggerates the inflammatory response through down-regulation of autophagy activity. Recombinant Klotho may have the therapeutic potential for suppression of valvular inflammation associated with CAVD progression.
Published Version
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