Proprotein convertase substilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein (LDL) receptor (LDLR) and thereby increases serum LDL-cholesterol (LDL-C). We have developed a humanized monoclonal antibody that recognizes the LDLR binding domain of PCSK9. This antibody, J16, and its precursor mouse antibody, J10, potently inhibit PCSK9 binding to the LDLR extracellular domain and PCSK9-mediated down-regulation of LDLR in vitro. In vivo, J10 effectively reduces serum cholesterol in C57BL/6 mice fed normal chow. J16 reduces LDL-C in healthy and diet-induced hypercholesterolemic cynomologous monkeys, but does not significantly affect high-density lipoprotein-cholesterol. Furthermore, J16 greatly lowered LDL-C in hypercholesterolemic monkeys treated with the HMG-CoA reductase inhibitor simvastatin. Our data demonstrate that anti-PCSK9 antibody is a promising LDL-C-lowering agent that is both efficacious and potentially additive to current therapies.

Background While biglycan and oxidized low-density lipoprotein (oxLDL) accumulation has been observed in calcific, stenotic aortic valves, their role in the pathogenesis of calcific aortic valve disease is poorly understood. We hypothesized that soluble biglycan induces the osteogenic response in human aortic valve interstitial cells (AVICs) via Toll-like receptor (TLR) 2 and TLR4, and mediates the pro-osteogenic effect of oxLDL. Methods and Results AVICs of stenotic valves express higher levels of biglycan. Stimulation of cells from normal valves with biglycan increased the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) among the chondrogenic/osterogenic markers examined, and caused accumulation of calcium deposits. TLR2 silencing, but not TLR4 silencing, reduced BMP-2 and ALP levels following biglycan stimulation although co-immunoprecipitation revealed that biglycan intercts with both TLR2 and TLR4. Biglycan induced the phosphorylation of ERK1/2, p38 MAPK and NF-κB. Inhibition of ERK1/2 markedly reduced the up-regulation of BMP-2 and ALP expression by biglycan while inhibition of p38 MAPK or NF-κB had a moderate effect. Stimulation of AVICs with oxLDL up-regulated biglycan expression and release. Knockdown neutralization of biglycan reduced the effect of oxLDL on BMP-2 and ALP expression. Conclusion Extracellular soluble biglycan induces the expression of BMP-2 and ALP in human AVICs primarily via TLR2 and contributes to the the pro-osteogenic effect of oxLDL. These findings highlight the potential role of soluble biglycan and oxLDL in the development of calcific aortic valve disease.

Although medical therapy remains the primary treatment modality for patients with pulmonary NTM disease, the selective use of pulmonary resection may reduce the incidence of symptomatic disease recurrence. The addition of thoracoscopic resection to treatment regimens for patients with Lady Windermere syndrome can be accomplished with minimal morbidity and mortality.