title: The opposing roles of nitric oxide and cGMP in the age-associated decline in rat testicular steroidogenesis.
abstract: The molecular mechanism of the aging-associated dysfunction of Leydig cells (LCs) is complex and poorly understood. In this study, we analyzed the contribution of nitric oxide (NO) and cGMP signaling to the age-dependent decline in LC function. Significant (>50%) decreases in serum, intratesticular, and LC androgens in aging rats (15-24 months) were accompanied by a proportional increase in NO production, an up-regulation of cGMP levels, and the expression of soluble guanylyl cyclase-1B and protein kinase G1 in LCs. In contrast, LC cAMP levels decreased with age, most likely reflecting the up-regulation of cAMP-specific phosphodiesterase expression. Moreover, the expression of genes encoding enzymes responsible for cholesterol transport and its conversion to T were reduced. Exposing LCs from aged animals to NO further increased cGMP levels and decreased cAMP and androgen production, whereas the addition of cell-permeable 8-bromoguanosine-cGMP alone had the opposite effect. In vivo inhibition of cGMP-specific phosphodiesterase-5 for 3 and 6 months in aged rats led to a partial restoration of androgens, NO, and cyclic nucleotide levels, as well as the expression of steroidogenic and NO/cGMP signaling genes. These results indicate that a progressive increase in NO production contributes to the age-dependent decrease in steroidogenesis in a cGMP-independent manner, whereas the sustained elevation in cGMP levels significantly slows the decline in LC function.
authors.affiliation: PhD, Reproductive Endocrinology and Signaling Group, University of Novi Sad, Novi Sad 21000, Serbia. tatjana.kostic@dbe.uns.ac.rs.
authors.forename: Srdjan J
authors.initials: SJ
authors.lastname: Sokanovic
authors.forename: Aleksandar Z
authors.initials: AZ
authors.lastname: Baburski
authors.forename: Marija M
authors.initials: MM
authors.lastname: Janjic
authors.forename: Natasa J
authors.initials: NJ
authors.lastname: Stojkov
authors.forename: Maja M
authors.initials: MM
authors.lastname: Bjelic
authors.forename: Dusan
authors.initials: D
authors.lastname: Lalosevic
authors.forename: Silvana A
authors.initials: SA
authors.lastname: Andric
authors.forename: Stanko S
authors.initials: SS
authors.lastname: Stojilkovic
authors.forename: Tatjana S
authors.initials: TS
authors.lastname: Kostic
mesh_terms: D000375:Aging; D000728:Androgens / Q000097:blood / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000378:metabolism; D005303:Fertility Agents, Male / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006162:Guanylate Cyclase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007985:Leydig Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013737:Testis / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000728:Androgens; D005303:Fertility Agents, Male; D058986:Phosphodiesterase 5 Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D000242:Cyclic AMP; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569721:Prkg1 protein, rat; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase