Down-regulation of neutral sphingomyelinase in androgen-dependent smooth muscle.
BACKGROUND
During puberty, proliferation of guinea pig seminal vesicle smooth muscle (SVM) is mediated by androgen-induced basal release of norepinephrine (NE), signaling through the post-junctional alpha1-adrenoceptor. In the adult, the SVM is terminally differentiated, such that cell number is androgen resistant. Sphingomyelinase activation generates second messenger ceramides, which in vascular smooth muscle have been reported to counter the alpha1-adrenoceptor-mediated contractile response and activate apoptosis. Accordingly, we hypothesized that SVM sphingomyelinase down-regulation by androgen may facilitate NE-induced proliferation and subsequent transition to the terminally differentiated state of the adult.


METHODS
Pre-pubertal and adult guinea pigs were orchiectomized and treated+/-dihydrotestosterone (DHT). SVM was harvested free of epithelium, frozen, and stored for enzymatic analyses. Using radioactive sphingomyelin substrate, optimized reaction conditions for both neutral and acidic sphingomyelinase were established and used to assay the enzymes.


RESULTS
Although acidic sphingomyelinase was stimulated by androgen in both the proliferative and amitotic phases of smooth muscle development, neutral sphingomyelinase was irreversibly reduced 35% at the time of DHT-induced proliferation.


CONCLUSIONS
Decreased concentrations of a second messenger ceramide attenuate apoptosis and increase sensitivity to alpha(1)-adrenoceptor-mediated mitogenic signaling. Therefore, DHT-dependent suppression of neutral sphingomyelinase activity may reduce ceramide concentrations and facilitate NE-dependent smooth muscle growth.
Durham
John P
JP
Department of Biochemistry, West Virginia University, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia 26506-9223, USA.
Mawhinney
Michael G
MG
D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009919:Orchiectomy; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology; D012669:Seminal Vesicles / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
D000728:Androgens; D002518:Ceramides; D018340:Receptors, Adrenergic, alpha-1; D013196:Dihydrotestosterone; D013108:Sphingomyelin Phosphodiesterase