Abstract 159: Androgen Deficiency Influences Matrix Metalloproteinase Expression and Intimal Hyperplasia Development After Vascular Injury
Objectives: Androgen deficiency (AD) is associated with increased risk of vascular disease, yet the molecular mechanisms remain unclear. Our group has previously shown testosterone regulates matrix metalloproteinases (MMP) in a dose-dependent manner in vitro. Here we investigated the role of AD and androgen replacement therapy (ART) on inflammatory cytokines and MMP-modulated intimal hyperplasia (IH) development in vivo.
Methods: Aged orchiectomized (AO) rats were implanted with increasing doses of testosterone pellets (TST; 0.5-150mg). ELISA and multiplex array determined serum TST and cytokine levels. Young intact (YI), Aged intact (AI), and AO rats given placebo (Plac) or TST supplementation underwent balloon angioplasty of the left common carotid following 14d ART. Tissue samples were collected 14d post-injury for Intima:Media (I:M) or MMP quantification.
Results: Therapeutic TST doses were achieved at 14d with 0.5, 2.5, 5, and 35mg pellets when compared to controls (Table 1). Interleukin family isoforms were elevated at sub-physiological TST levels but returned to control levels with physiological TST (Table 2). I:M was decreased in AI and physiological TST levels compared to YI (Fig 1). I:M was increased with sub- and supra-physiological TST. Injury-induced expression of MMP-2 was highest in AI and physiological TST conditions, though these values were not significant (Table 3). Analysis of other MMP isoforms is ongoing.
Conclusions: We demonstrated that low testosterone levels increase interleukin inflammatory signaling, regulate MMP expression, and increase IH development in vivo. This effect is reversed by physiologic testosterone supplementation. AD could be playing a role in vascular disease via MMP regulatory mechanisms under the control of inflammatory signaling cascades. Future studies will examine targeted inhibition of inflammatory-modulated MMP mechanisms in the prevention of dysfunctional vascular remodeling.
Author Disclosures: B.M. Freeman: None. D.J.H. Mountain: None. T.C. Brock: None. J.R. Chapman: None. S.S. Kirkpatrick: None. J.D. Arnold: None. S.L. Stevens: None. M.H. Goldman: None. M.B. Freeman: None. F.A. Klein: None. O.H. Grandas: None.
- © 2014 by American Heart Association, Inc.