Lysophosphatidylcholine activates the Akt pathway to upregulate extracellular matrix protein production in human aortic valve cells.

ABSTRACT

BACKGROUND: Overproduction of extracellular matrix (ECM) protein by aortic valve interstitial cells (AVICs) plays an important role in valvular sclerosis (thickening) associated with the early pathobiology of aortic stenosis. Accumulation of oxidized low-density lipoprotein (oxLDL) is observed in sclerotic aortic valve and may have a mechanistic role in valvular disease progression. Lysophosphatidylcholine (LysoPC) is a component of oxLDL and has multiple biological activities. This study was to test the hypothesis that oxLDL and LysoPC upregulate ECM protein production in human AVICs. METHODS AND RESULTS: AVICs were isolated from normal human aortic valves. Cells were treated with oxLDL (40 µg/mL) or LysoPC (40 µmol/L). Immunoblotting was applied to analyze ECM proteins (collagens I and III and biglycan) in cell lysate and Picrosirius red staining was used to examine collagen deposition. Both oxLDL and LysoPC upregulated the production of biglycan and collagen I. The upregulation of ECM proteins by LysoPC was preceded by the phosphorylation of Akt and ERK1/2. Inhibition of Akt markedly reduced the effect of LysoPC on ECM protein production and collagen deposition. However, inhibition of ERK1/2 had no effect. CONCLUSIONS: LysoPC upregulates the production of biglycan and collagen I in human AVICs and may mediate the effect of oxLDL on ECM protein production. The Akt pathway appears to be critical in mediating the effect of LysoPC. oxLDL accumulation and generation of LysoPC in the aortic valve tissue may contribute to the mechanism of valvular sclerosis associated with the development and progression of aortic stenosis.