PS-BPB01-7: ANGIOTENSIN II INDUCES AORTIC RUPTURE AND DISSECTION IN OSTEOPROTEGERIN-DEFICIENT MICE

Abstract

Background: The biological mechanism of action for osteoprotegerin (OPG), a soluble decoy receptor for the receptor activator of nuclear factor kappa-B ligand (RANKL) in the vascular structure, has not been elucidated. The study aim was to determine if OPG affects aortic structural integrity in angiotensin II-induced hypertension. Methods and Results: Mortality was higher (P < 0.0001 by Log-rank test) in 8-week-old male homozygotes of OPG gene knockout (OPG -/- mice given subcutaneous administration of angiotensin II (1,000 ng/kg/min) for 28 days, with an incidence of 21% fatal aortic rupture (Chi-square, 8.024, P = 0.005), and 23% aortic dissection (Chi-square, 4.285, P = 0.038), than in age-matched wild type mice. The absence of OPG was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with 2.5-fold increased periostin expression and soluble RANKL concentrations. PEGylated human recombinant OPG administration decreased all-causes mortality (-22%, P < 0.001 by Log-rank test), the incidence of fatal aortic rupture (-13%, P = 0.08), and aortic dissection (-23%, P < 0.001) with decreasing numbers of elastin breaks (P = 0.0539) at the supra-renal aorta, periostin expressions (P = 0.0011), and soluble RANKL concentrations (P = 0.0012) in angiotensin II-infused OPG-/- mice. Conclusions: These data suggest that OPG protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting RANKL activity and periostin expression.