Abstract 16764: Aging-Related Myofibroblastic Transition in Aortic Valve Interstitial Cells Elevates Valvular Osteogenic Response to Oxidized Low Density Lipoprotein

Abstract

Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder in the elderly. The pathobiology of this disease involves chronic inflammation, fibrosis and calcification. However, the molecular mechanism underlying CAVD progression remains obscure. Diseased aortic valves display higher levels of oxidized low-density lipoprotein (oxLDL), and oxLDL has the potential to interact with Toll-like receptors (TLRs) in aortic valve interstitial cells (AVICs) to elevate cellular osteogenic activity. We tested the hypotheses that aging-related myofibroblastic transition in AVICs elevates valvular osteogenic response to oxLDL. Methods and Results: AVICs from normal valves of young (20-30 years old) and older (60-70 years old) people were treated with oxLDL (40 μg/ml) for 3-14 days in vitro. OxLDL had a greater effect on the up-regulation of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP), as well as on the induction of calcium deposition, in AVICs from older donors. The exaggerated pro-osteogenic effect of oxLDL in AVICs of older donors was associated with over-expression of myofibroblastic biomarker α-smooth muscle actin (α-SMA), and knockdown of α-SMA with lentiviral shRNA markedly attenuated the osteogenic response. Further, oxLDL induced greater activation of ERK1/2 and NF-κB in AVICs of older donors. Inhibition of ERK1/2 or NF-κB greatly diminished the effect of oxLDL on BMP-2 and ALP expression in AVICs from both young and older donors. Conclusions: The results of this study show that oxLDL exerts a greater impact on AVICs of older subjects to elevate the pro-osteogenic activity through activation of the ERK1/2 and NF-κB pathways. AVIC myofibroblastic transition associated with aging is responsible, at least in part, for the elevated osteogenic response to oxLDL. These findings reveal a novel mechanism underlying CAVD pathogenesis and indicate that suppression of AVIC myofibroblastic transition in the elderly patients may have the therapeutic potential for suppression of CAVD progression.