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Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification.

Zhu D, Hadoke PW, Wu J, Vesey AT, Lerman DA, Dweck MR, Newby DE, Smith LB, MacRae VE - Sci Rep (2016)

Bottom Line: Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT.Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression.Androgen signalling may represent a novel potential therapeutic target for clinical intervention.

View Article: PubMed Central - PubMed

Affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, EH25 9RG, UK.

ABSTRACT
Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.

No MeSH data available.


Related in: MedlinePlus

Altered mRNA expression of osteogenic genes in SM-ARKO VSMCs.Fold change in the mRNA expression of (a) Osterix (b) Alpl and (c) Mgp in SM-ARKO VSMCs versus WT control cells (n = 5). Results are presented as mean + /− S.E.M ***P < 0.001 compared with control.
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f4: Altered mRNA expression of osteogenic genes in SM-ARKO VSMCs.Fold change in the mRNA expression of (a) Osterix (b) Alpl and (c) Mgp in SM-ARKO VSMCs versus WT control cells (n = 5). Results are presented as mean + /− S.E.M ***P < 0.001 compared with control.

Mentions: To examine whether testosterone-stimulated VSMC calcification is mediated through the AR, further studies were undertaken using cells derived from VSMC-specific AR-ablated (SM-ARKO) mice. Protein expression studies confirmed AR ablation in the VSMCs (Fig. 3a). Furthermore, testosterone exposure notably up-regulated AR protein expression in WT VSMCs, whereas AR expression remained absent in comparably-treated SM-ARKO cells (Fig. 3a). Additional studies revealed a marked reduction in Esr2 mRNA expression in SM-ARKO mice versus WT controls (0.4 fold; P < 0.05; Fig. 3b), whereas Esr1 expression remained unaltered (Fig. 3c). Consistent with our earlier observations (Fig. 2a), 100 nM testosterone significantly increased VSMC calcification in WT cells. However, testosterone-induced calcification was blunted in SM-ARKO cells (0.52 fold; P < 0.05; Fig. 3d). Consistent with these data, SM-ARKO VSMCs showed a significant reduction in Osterix mRNA expression (0.85 fold; P < 0.001; Fig. 4a). However, intriguingly, a counter-intuitive increase in Alpl was observed (3.3 fold; Fig. 4b, P < 0.001), with a concomitant decrease in the mineralisation inhibitor Mgp (0.5 fold; Fig. 4c, P < 0.001).


Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification.

Zhu D, Hadoke PW, Wu J, Vesey AT, Lerman DA, Dweck MR, Newby DE, Smith LB, MacRae VE - Sci Rep (2016)

Altered mRNA expression of osteogenic genes in SM-ARKO VSMCs.Fold change in the mRNA expression of (a) Osterix (b) Alpl and (c) Mgp in SM-ARKO VSMCs versus WT control cells (n = 5). Results are presented as mean + /− S.E.M ***P < 0.001 compared with control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837411&req=5

f4: Altered mRNA expression of osteogenic genes in SM-ARKO VSMCs.Fold change in the mRNA expression of (a) Osterix (b) Alpl and (c) Mgp in SM-ARKO VSMCs versus WT control cells (n = 5). Results are presented as mean + /− S.E.M ***P < 0.001 compared with control.
Mentions: To examine whether testosterone-stimulated VSMC calcification is mediated through the AR, further studies were undertaken using cells derived from VSMC-specific AR-ablated (SM-ARKO) mice. Protein expression studies confirmed AR ablation in the VSMCs (Fig. 3a). Furthermore, testosterone exposure notably up-regulated AR protein expression in WT VSMCs, whereas AR expression remained absent in comparably-treated SM-ARKO cells (Fig. 3a). Additional studies revealed a marked reduction in Esr2 mRNA expression in SM-ARKO mice versus WT controls (0.4 fold; P < 0.05; Fig. 3b), whereas Esr1 expression remained unaltered (Fig. 3c). Consistent with our earlier observations (Fig. 2a), 100 nM testosterone significantly increased VSMC calcification in WT cells. However, testosterone-induced calcification was blunted in SM-ARKO cells (0.52 fold; P < 0.05; Fig. 3d). Consistent with these data, SM-ARKO VSMCs showed a significant reduction in Osterix mRNA expression (0.85 fold; P < 0.001; Fig. 4a). However, intriguingly, a counter-intuitive increase in Alpl was observed (3.3 fold; Fig. 4b, P < 0.001), with a concomitant decrease in the mineralisation inhibitor Mgp (0.5 fold; Fig. 4c, P < 0.001).

Bottom Line: Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT.Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression.Androgen signalling may represent a novel potential therapeutic target for clinical intervention.

View Article: PubMed Central - PubMed

Affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, EH25 9RG, UK.

ABSTRACT
Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.

No MeSH data available.


Related in: MedlinePlus