Low testosterone elevates interleukin family cytokines in a rodent model: a possible mechanism for the potentiation of vascular disease in androgen-deficient males.
BACKGROUND
Androgen deficiency (AD) is associated with increased risk of atherosclerosis, cardiovascular, and peripheral arterial disease. Although the biochemical and molecular mechanisms underlying this risk remain unclear, higher testosterone (TST) levels correlate to significant immunoprotective molecular and cellular responses. Our group has previously demonstrated that female sex hormones influence vascular pathogenesis via inflammatory-modulated matrix metalloproteinase (MMP) regulation. Here we investigated the role of AD and androgen replacement therapy in the modulation of these hormonally responsive pathways that could be playing a role in the development of vascular pathogenesis.


METHODS
Aged orchiectomized male rats underwent TST supplementation per controlled release pellet implantation (0-150 mg). Young and aged intact groups served as controls. Serum was collected at 0-4 wk and analyzed by enzyme-linked immunosorbent assays, qualitative cytokine screening, and quantitative multiplex analyses. Human aortic smooth muscle cells were treated with 4,5α-dihydrotestosterone (DHT; 0-3000 nM) before or after interleukin 1β (IL-1β; 5 ng/mL) stimulation. Quantitative polymerase chain reaction and in-gel zymography was used to assay the effect on MMP expression and activity.


RESULTS
Subphysiological, physiological, and supraphysiological levels of TST were achieved with 0.5, 2.5, and 35 mg TST pellet implants in vivo, respectively. Inflammatory arrays indicated that interleukin cytokines, specifically IL-2, IL-6, IL-10, IL-12, and IL-13, were elevated at subphysiological level of TST, whereas TST supplementation decreased interleukins. Supraphysiological TST resulted in a significant increase in MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in vivo. Pretreatment with IL-1β slightly increased membrane type 1-MMP (MT1-MMP) and MMP-2 expression at low to mid-level DHT exposure in vitro, although these trends were not statistically significant.


CONCLUSIONS
Here we demonstrate AD is a proinflammatory modulator and indicate that MMP-independent mechanisms may play a role downstream of AD-induced inflammatory signaling in dysfunctional vascular remodeling. Future in vivo studies will examine AD and TST supplementation in acute inflammatory response to vascular injury and in MMP-modulated vascular disease.
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee.
Brian M
BM
Freeman
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee.
Deidra J H
DJ
Mountain
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee.
Timothy C
TC
Brock
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee.
Jason R
JR
Chapman
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee.
Stacy S
SS
Kirkpatrick
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee.
Michael B
MB
Freeman
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee.
Frederick A
FA
Klein
Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee. Electronic address: ograndas@utmck.edu.
Oscar H
OH
Grandas
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007378:Interleukins / Q000097:blood*; D008297:Male; D020782:Matrix Metalloproteinases / Q000502:physiology; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood / Q000172:deficiency*; D014652:Vascular Diseases / Q000209:etiology*
D053583:Interleukin-1beta; D007378:Interleukins; D013739:Testosterone; D020782:Matrix Metalloproteinases
Androgen deficiency; Inflammation; Interleukins; Matrix metalloproteinase; Testosterone; Vascular disease