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PO3-3-46

Sex Difference of Cardiovascular Death in the 2/3 Nephrectomized-Nitric Oxide Synthases Deficient Mice: Involvement of Androgen

[Speaker] Mayuko Sakanashi:1,2
[Co-author] Yuji Taira:1, Toshihiro Matsuzaki:1, Junko Nakasone:1, Haruaki Kubota:1, Katsuhiko Noguchi:1, Masato Tsutsui:1
1:Department of Pharmacology, Graduate school of medicine, University of the Ryukyus, Japan, 2:Department of Pharmacy, Kinjo Gakuin University, Japan

Background: We made the n/i/eNOS knockout (KO) mice which neuronal (n), inducible (i) and endothelial (e) nitric oxide synthase (NOS) genes are completely disrupted. Recently, we found that the 2/3 nephrectomy (NX) caused an early onset of acute myocardial infarction in the n/i/eNOS KO mice, suggesting that impaired NO production plays an important role in the association between the kidney and the heart. The aim of this study was to determine whether sex difference is present in the mortality of the 2/3NX n/i/eNOS KO mice, and to clarify what mechanisms are involved.
Methods: The male and female mice (8 weeks) underwent 2/3 nephrectomy with or without gonadectomy. The tube containing crystalline testosterone was implanted into a part of the gonadectomized mice. Four weeks after 2/3NX, systolic blood pressures were measured by tail cuff method and the plasma lipid profiles were measured by colorimetric method.
Results: Since approximately 90% of male n/i/eNOS KO mice died of myocardial infarction in our previous study, the death rate was used as an index of the incidence of myocardial infarction. The mortality of the male 2/3NX n/i/eNOS KO mice was markedly higher than that of the female mice. Ovariectomy did not affect the mortality rate of female 2/3NX n/i/eNOS KO mice, whereas orchidectomy significantly reduced that of male 2/3NX n/i/eNOS KO mice. In the male 2/3NX n/i/eNOS KO mice, significantly lowering effects of systolic blood pressures and fasting blood glucose levels were associated with orchidectomy. Importantly, these beneficial effects of orchiectomy were reversed by chronic treatment with testosterone.
Conclusions: Gender difference was present in the mortality of the 2/3NX n/i/eNOS KO mice: the male mice have markedly higher mortality rate than the female mice. Deleterious effects of testosterone, but not beneficial effects of estrogen, appear to be involved in the mechanisms of the sex difference. A large clinical study reported that supplementation with testosterone did not decrease, but rather increased cardiovascular death in aged male patients with coronary artery disease and with low plasma testosterone levels. The present findings may explain in part these unexpected outcomes.
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