Osteoprotegerin: a pathological role in human abdominal aortic aneurysm

摘要: Rupture of Abdominal Aortic Aneurysm (AAA) is the end-stage, catastrophic failure aneurysmal aortic wall and associated with a mortality rate up to 95 percent. Presently, surgery only treatment option available but carries it five percent usually reserved for repair aneurysms showing high probability rupture. What required AAA, essentially basis research in this area, understand pathology disease well enough so that non-surgical intervention aimed at inhibiting small aneurysm progression can be developed. The lack non-invasive medical disease, especially initial stages development, stems from an incomplete understanding its pathogenesis. Despite extensive laboratory clinical research, precise mechanisms leading formation remain unclear. The hallmark features are degradation fragmentation medial extracellular matrix (ECM), significant reduction smooth muscle cell (SMC) density, believed marked cellular inflammatory response also observed tissue. A newly identified member tumour necrosis factor receptor superfamily known as osteoprotegerin (OPG) constitutively expressed within human artery and, under pathological conditions, upregulated vascular disease. Elaboration on involvement OPG AAA will determine potential pharmacological target focus study was whether might important development AAA. Two hypotheses were proposed: 1. Expression aorta 2. Osteoprotegerin actively promotes phenotype specific aims to: a) Assess relationship between concentration presence aneurysm b) Define possible mechanism(s) by which may functionally active promotion development c) Modulate expression assess effect development Serum correlated growth 146 men followed ultrasound 3 years (R=0.20; P=0.04), demonstrated predictor expansion multiple-regression analysis (P=0.02; coefficient 1.33, SE 0.51) model consisting patient age, diabetic status, smoking history, diameter, serum cholesterol, C-reactive protein. Western showed 3-fold, 8-fold, 12-fold greater concentrations biopsies compared age gender-matched atherosclerotic narrowed aorta (AOD; 1.4±0.1 ng/mg tissue vs 0.5±0.1 tissue; P=0.002), post-mortem non-diseased abdominal (PAA; 0.2±0.1 P<0.001), thoracic (TA; 0.1±0.06 respectively. Resident cells (VSMC) infiltrating macrophages primary sources media. association confirmed animal experimental formation, levels protein 4-fold non-aneurysmal Furthermore, strongly vessel diameter. Healthy VSMC incubated recombinant (0-20 ng rhOPG/10 ⁵ cells/ml/24h) developed defined dose-dependent impaired proliferation (P<0.001), increased apoptosis (P<0.01), decreased interleukin (IL)-6 metalloproteinase (MMP)-9 activity (P=0.01). Gene OPG-treated reflected these results exhibiting down-regulation genes survival, up-regulation negatively regulate promote death. Incubation monocytic resulted 2-fold increase IL-6 production lipopolysaccharide (LPS)-activated (P=0.005). In addition, (1 ng/10 acted induce MMP-9 1.5-fold MMP-2 (P=0.01) resting cells. Treatment culture angiotensin II blocker, Irbesartan, peroxisome proliferator-activated gamma (PPARγ) ligands, Pioglitazone Rosiglitazone, inhibited 50%, reducing cytokine, proteolytic enzyme production. effects produced thiazolidinedione ex vivo reproduced vivo. Both MMP mouse down-regulated significantly medication. This demonstrates first time identifies key role normal wall. ability existing medication limit action potentially opens therapeutic pathway through humans targeting arterial OPG.