Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis
Sickle cell disease (SCD)‐associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone...
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| Veröffentlicht in: | Andrology (Oxford) 2018-01, Vol.6 (1), p.184-191 |
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| creator | Musicki, B. Karakus, S. Akakpo, W. Silva, F. H. Liu, J. Chen, H. Zirkin, B. R. Burnett, A. L. |
| description | Sickle cell disease (SCD)‐associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild‐type (WT) mice were implanted with testosterone pellets, which release 1.2 μg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone‐responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α‐smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser‐92, eNOS at Ser‐1177, neuronal (n) NOS at Ser‐1412, and Akt at Ser‐473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p |
| doi_str_mv | 10.1111/andr.12442 |
| format | Article |
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H. ; Liu, J. ; Chen, H. ; Zirkin, B. R. ; Burnett, A. L.</creator><creatorcontrib>Musicki, B. ; Karakus, S. ; Akakpo, W. ; Silva, F. H. ; Liu, J. ; Chen, H. ; Zirkin, B. R. ; Burnett, A. L.</creatorcontrib><description>Sickle cell disease (SCD)‐associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild‐type (WT) mice were implanted with testosterone pellets, which release 1.2 μg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone‐responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α‐smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser‐92, eNOS at Ser‐1177, neuronal (n) NOS at Ser‐1412, and Akt at Ser‐473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P‐PDE5 (Ser‐92), PDE5, P‐eNOS (Ser‐1177), and P‐Akt (Ser‐473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P‐nNOS (Ser‐1412), eNOS, nNOS, or α‐smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis.</description><identifier>ISSN: 2047-2919</identifier><identifier>EISSN: 2047-2927</identifier><identifier>DOI: 10.1111/andr.12442</identifier><identifier>PMID: 29145710</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Akt ; Androgens ; Anemia, Sickle Cell - complications ; Animals ; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism ; Drug therapy ; eNOS phosphorylation ; Male ; Mice ; Mice, Transgenic ; Nitric oxide ; Nitric Oxide Synthase Type III - metabolism ; nNOS phosphorylation ; Penis - drug effects ; Penis - metabolism ; Priapism - etiology ; Priapism - metabolism ; Protein expression ; Proteins ; Rodents ; Smooth muscle ; Testosterone ; Testosterone - pharmacology ; Up-Regulation</subject><ispartof>Andrology (Oxford), 2018-01, Vol.6 (1), p.184-191</ispartof><rights>2017 American Society of Andrology and European Academy of Andrology</rights><rights>2017 American Society of Andrology and European Academy of Andrology.</rights><rights>Andrology © 2018 American Society of Andrology and European Academy of Andrology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4482-fa0be4c8e52ff9151994613689278814251345a71e1ffaca066ef41171d85c0a3</citedby><cites>FETCH-LOGICAL-c4482-fa0be4c8e52ff9151994613689278814251345a71e1ffaca066ef41171d85c0a3</cites><orcidid>0000-0002-0437-980X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fandr.12442$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fandr.12442$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29145710$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Musicki, B.</creatorcontrib><creatorcontrib>Karakus, S.</creatorcontrib><creatorcontrib>Akakpo, W.</creatorcontrib><creatorcontrib>Silva, F. H.</creatorcontrib><creatorcontrib>Liu, J.</creatorcontrib><creatorcontrib>Chen, H.</creatorcontrib><creatorcontrib>Zirkin, B. R.</creatorcontrib><creatorcontrib>Burnett, A. L.</creatorcontrib><title>Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis</title><title>Andrology (Oxford)</title><addtitle>Andrology</addtitle><description>Sickle cell disease (SCD)‐associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild‐type (WT) mice were implanted with testosterone pellets, which release 1.2 μg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone‐responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α‐smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser‐92, eNOS at Ser‐1177, neuronal (n) NOS at Ser‐1412, and Akt at Ser‐473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P‐PDE5 (Ser‐92), PDE5, P‐eNOS (Ser‐1177), and P‐Akt (Ser‐473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P‐nNOS (Ser‐1412), eNOS, nNOS, or α‐smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis.</description><subject>Akt</subject><subject>Androgens</subject><subject>Anemia, Sickle Cell - complications</subject><subject>Animals</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism</subject><subject>Drug therapy</subject><subject>eNOS phosphorylation</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Nitric oxide</subject><subject>Nitric Oxide Synthase Type III - metabolism</subject><subject>nNOS phosphorylation</subject><subject>Penis - drug effects</subject><subject>Penis - metabolism</subject><subject>Priapism - etiology</subject><subject>Priapism - metabolism</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Smooth muscle</subject><subject>Testosterone</subject><subject>Testosterone - pharmacology</subject><subject>Up-Regulation</subject><issn>2047-2919</issn><issn>2047-2927</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1uFDEMxyNERavSCw-AInFBSFuSbDKTuSBV_aCVqhZBOUdp1rNNySRDMlPYt-gj4-m2y8cBK1Is-5e_7ZiQV5ztc7T3Ni7yPhdSimdkRzBZz0Qj6ucbnzfbZK-UW4ampyNekG0MS1VztkPur6AMqQyQUwSaoQ_WQQdxoD7SIdtYlhC9o8W7bwGogxBo5x16KQ45hUL77G2PhHWDv_PDimJHdOwzLMdgByj009GxovATI6X4FB_ycHH55feLqdQN0B4rlZdkq7WhwN7jvUu-nhxfHZ7Ozi8_nh0enM-clFrMWsuuQToNSrRtwxVvGlnxeaVxeK25FIrPpbI1B9621llWVdBKzmu-0MoxO98lH9a6_XjdwcLhyNkGg9N0Nq9Mst78nYn-xizTnVG1VKJWKPD2USCn7yP-oul8mf7HRkhjMbypKjGXTFSIvvkHvU1jjjgeUppVWjfNJPhuTbmcSsnQbprhzEy7NtOuzcOuEX79Z_sb9GmzCPA18MMHWP1HyhxcHH1ei_4Ceia2ZA</recordid><startdate>201801</startdate><enddate>201801</enddate><creator>Musicki, B.</creator><creator>Karakus, S.</creator><creator>Akakpo, W.</creator><creator>Silva, F. H.</creator><creator>Liu, J.</creator><creator>Chen, H.</creator><creator>Zirkin, B. R.</creator><creator>Burnett, A. L.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0437-980X</orcidid></search><sort><creationdate>201801</creationdate><title>Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis</title><author>Musicki, B. ; Karakus, S. ; Akakpo, W. ; Silva, F. H. ; Liu, J. ; Chen, H. ; Zirkin, B. R. ; Burnett, A. L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4482-fa0be4c8e52ff9151994613689278814251345a71e1ffaca066ef41171d85c0a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Akt</topic><topic>Androgens</topic><topic>Anemia, Sickle Cell - complications</topic><topic>Animals</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism</topic><topic>Drug therapy</topic><topic>eNOS phosphorylation</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Nitric oxide</topic><topic>Nitric Oxide Synthase Type III - metabolism</topic><topic>nNOS phosphorylation</topic><topic>Penis - drug effects</topic><topic>Penis - metabolism</topic><topic>Priapism - etiology</topic><topic>Priapism - metabolism</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Rodents</topic><topic>Smooth muscle</topic><topic>Testosterone</topic><topic>Testosterone - pharmacology</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Musicki, B.</creatorcontrib><creatorcontrib>Karakus, S.</creatorcontrib><creatorcontrib>Akakpo, W.</creatorcontrib><creatorcontrib>Silva, F. H.</creatorcontrib><creatorcontrib>Liu, J.</creatorcontrib><creatorcontrib>Chen, H.</creatorcontrib><creatorcontrib>Zirkin, B. R.</creatorcontrib><creatorcontrib>Burnett, A. L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Andrology (Oxford)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Musicki, B.</au><au>Karakus, S.</au><au>Akakpo, W.</au><au>Silva, F. H.</au><au>Liu, J.</au><au>Chen, H.</au><au>Zirkin, B. R.</au><au>Burnett, A. L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis</atitle><jtitle>Andrology (Oxford)</jtitle><addtitle>Andrology</addtitle><date>2018-01</date><risdate>2018</risdate><volume>6</volume><issue>1</issue><spage>184</spage><epage>191</epage><pages>184-191</pages><issn>2047-2919</issn><eissn>2047-2927</eissn><abstract>Sickle cell disease (SCD)‐associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5. Adult male transgenic Berkeley sickle cell (Sickle) and wild‐type (WT) mice were implanted with testosterone pellets, which release 1.2 μg testosterone/day for 21 days, or vehicle. After 21 days, animals underwent erectile function assessment followed by collection of blood for serum testosterone measurements, penes for molecular analysis, and seminal vesicles as testosterone‐responsive tissue. Serum testosterone levels were measured by radioimmunoassay; protein expressions of PDE5, α‐smooth muscle actin, eNOS and nNOS, and phosphorylation of PDE5 at Ser‐92, eNOS at Ser‐1177, neuronal (n) NOS at Ser‐1412, and Akt at Ser‐473 were measured by Western blot in penile tissue. Testosterone treatment reversed downregulated serum testosterone levels and increased (p < 0.05) the weight of seminal vesicles in Sickle mice to levels comparable to that of WT mice, indicating restored testosterone levels in Sickle mice. Testosterone treatment reduced (p < 0.05) prolonged detumescence in Sickle mice and normalized downregulated P‐PDE5 (Ser‐92), PDE5, P‐eNOS (Ser‐1177), and P‐Akt (Ser‐473) protein expressions in the Sickle mouse penis. Testosterone treatment did not affect P‐nNOS (Ser‐1412), eNOS, nNOS, or α‐smooth muscle actin protein expressions in the Sickle mouse penis. In conclusion, in the mouse model of human SCD, increasing testosterone to eugonadal levels reduced priapic activity and reversed impaired Akt/eNOS activity and PDE5 protein expression in the penis.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>29145710</pmid><doi>10.1111/andr.12442</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-0437-980X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Akt Androgens Anemia, Sickle Cell - complications Animals Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism Drug therapy eNOS phosphorylation Male Mice Mice, Transgenic Nitric oxide Nitric Oxide Synthase Type III - metabolism nNOS phosphorylation Penis - drug effects Penis - metabolism Priapism - etiology Priapism - metabolism Protein expression Proteins Rodents Smooth muscle Testosterone Testosterone - pharmacology Up-Regulation |
| title | Testosterone replacement in transgenic sickle cell mice controls priapic activity and upregulates PDE5 expression and eNOS activity in the penis |
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