Abstract 470: Androgen Receptor Activation Protects Against Vascular Remodeling in Male Mice
Background: Andropause promotes cardiovascular diseases in elderly individuals. We previously reported that the androgen-androgen receptor (AR) system plays important roles in physiological cardiac growth and angiotensin (Ang) II-induced cardiac remodeling. However, it remains unclear whether the androgen-AR system is involved in the vascular remodeling induced by Ang II.
Methods and Results: Twenty-five-week-old AR knockout (ARKO) male mice and littermate wild-type (WT) male mice were divided into two groups: a group in which Ang II (2mg/kg/day) was administered for 2 weeks and a group that was received a sham operation. No structural differences in the coronary artery and thoracic aorta between WT mice and ARKO mice were observed in the sham operation group, whereas Ang II stimulation markedly enhanced both perivascular fibrosis and medial thickening in ARKO mice compared to those in WT mice. Levels of oxidative stress markers, such as thiobarbital reactive substances (TBARS) and dihydroethidium (DHE) staining, in the aorta as well as urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) excretion levels were higher in Ang II-treated ARKO mice than in Ang II-treated WT mice. Gene expression levels of TGF-beta 1 and NAD(P)H oxidase subunits, gp91phox, p22phox, p67phox and p47phox, were significantly higher in Ang II-treated ARKO mice than in Ang II-treated WT mice. The phosphorylation of c-Jun N-terminal kinase (JNK) and Smad2/3 in Ang II-treated ARKO mice was more enhanced than that in WT mice. Furthermore, levels of nitric oxide (NO) bioavailability markers, including urinary NOx, and levels of phosphorylation and expression of aortic endothelial NO synthase (eNOS) in ARKO mice were significantly lower than those in WT mice regardless of Ang II stimulation.
Conclusion: AR-mediated androgen action protects against vascular remodeling via pleiotropic effects regulating oxidative stress JNK, TGF-beta 1/Smad pathway and nitric oxide bioavailability.