Abstract 12451: Monocytes Enhance Inflammatory Responses to Soluble Matrilin-2 in Human Aortic Valve Interstitial Cells via the Interaction of β 2 -integrin With ICAM-1

Abstract

Calcific aortic valve disease (CAVD) is a slow progressive disease. Chronic inflammation plays a crucial role in CAVD progression. Monocyte infiltration and macrophage accumulation are found in calcified aortic valves. Soluble extracellular matrix proteins can act as damage-associated molecular patterns to induce the pathobiology associated with CAVD in aortic valve interstitial cells (AVICs). While human AVICs exhibit inflammatory response to soluble matrilin-2, the impact of monocytes on this response is unknown. We hypothesized that monocytes enhance AVIC inflammatory response to soluble matrilin-2 by a mechanism involving cell-cell interaction. Methods and Results: Human AVICs isolated from normal aortic valves were cultured alone or cocultured with monocytes in the absence or presence of recombinant matrilin-2 (1, 2 or 4 μg/ml). AVIC expression of ICAM-1 and IL-6 following an exposure to any dose of matrilin-2 was markedly enhanced by the presence of monocytes although matrilin-2 in the tested dose range had no effect on monocyte production of ICAM-1 or IL-6. Monocytes adhered to AVICs following matrilin-2 stimulation. Interestingly, matrilin-2 up-regulated the expression of β 2 -integrin in monocytes and ICAM-1 in AVICs. Neutralization of β 2 -integrin or ICAM-1 in coculture with specific antibody reduced the number of monocytes adhering to AVICs and suppressed the expression of ICAM-1 and IL-6 . Conversely, addition of β 2 -integrin CD18 enhanced the expression of ICAM-1 and IL-6 in AVICs exposed to matrilin-2. Further, stimulation of coculture with matrilin-2 induced greater YAP and NF-κB phosphorylation compared to AVIC monoculture. Inhibition of either YAP or NF-κB markedly suppressed the inflammatory response to matrilin-2 in coculture. Conclusions: Monocyte β 2 -integrin interacts with AVIC ICAM-1 to augment AVIC inflammatory response to soluble matrilin-2 through enhancing the activation of YAP and NF-κB signaling pathways. Infiltrated monocytes may promote valvular inflammation through cell-cell interaction with AVICs to enhance their sensitivity to damage - associated molecular patterns.