Testosterone Rescues the De‐Differentiation of Smooth Muscle Cells Through Serum Response Factor/Myocardin

• Published in: Journal of cellular physiology Vol. 232; no. 10; pp. 2806 - 2817
• Main Authors: Leimgruber, Carolina, Quintar, Amado A., Peinetti, Nahuel, Scalerandi, María V., Nicola, Juan P., Miano, Joseph M., Maldonado, Cristina A.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.10.2017
• Subjects: Actins - metabolism; Androgens; Animals; Calcium-Binding Proteins - metabolism; Calponins; Cell Dedifferentiation - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Differentiation; Dose-Response Relationship, Drug; Endotoxins; Gene expression; Homeostasis; Interleukin 6; Interleukin-6 - metabolism; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Microfilament Proteins - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Normalizing; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; Prostate; Rats, Wistar; RNA Interference; Serum response factor; Signal Transduction - drug effects; siRNA; Smooth muscle; Structure-function relationships; Testosterone; Testosterone - pharmacology; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.25679

Prostatic smooth muscle cells (pSMCs) differentiation is a key factor for prostatic homeostasis, with androgens exerting multiple effects on these cells. Here, we demonstrated that the myodifferentiator complex Srf/Myocd is up‐regulated by testosterone in a dose‐dependent manner in primary cultures of rat pSMCs, which was associated to the increase in Acta2, Cnn1, and Lmod1 expressions. Blocking Srf or Myocd by siRNAs inhibited the myodifferentiator effect of testosterone. While LPS led to a dedifferentiated phenotype in pSMCs, characterized by down‐regulation of Srf/Myocd and smooth muscle cell (SMC)‐restricted genes, endotoxin treatment on Myocd‐overexpressing cells did not result in phenotypic alterations. Testosterone at a physiological dose was able to restore the muscular phenotype by normalizing Srf/Myocd expression in inflammation‐induced dedifferentiated pSMCs. Moreover, the androgen reestablished the proliferation rate and IL‐6 secretion increased by LPS. These results provide novel evidence regarding the myodifferentiating role of testosterone on SMCs by modulating Srf/Myocd. Thus, androgens preserve prostatic SMC phenotype, which is essential to maintain the normal structure and function of the prostate. J. Cell. Physiol. 232: 2806–2817, 2017. © 2016 Wiley Periodicals, Inc. Androgens favor a contractile phenotype on smooth muscle cells that relies on the Myocd/SRF myodifferentiator complex, with this role being critical for cellular homeostasis and pathophysiology.