Interaction of age and gender on NO bioavailability

描述（申请人提供）：高龄和男性是心血管疾病的危险因素，与血管内皮功能障碍相关。虽然介导内皮功能障碍的分子机制尚未完全阐明，但有人认为与一氧化氮（NO）生物利用度的降低有关。NO的下降可能是由于(1)内皮NO合成酶（NOS 3）活性/表达的改变，(2)NOS 3底物/辅助因子可用性的改变，或(3)超氧化物对NO的降解增加。这一建议的基本原理是，年龄对一氧化氮调节和一氧化氮生物利用度影响的性别差异可能导致内皮功能障碍的性别差异。本提案的目的是研究年龄增长如何改变雄性和雌性大鼠的NOS 3系统和氧化应激。我们假设随着年龄的增长，一氧化氮调节发生改变，氧化应激增加导致一氧化氮减少。此外，我们假设女性将被“保护”免受这些衰老的影响，因此男性将比女性经历更大的NO下降。本研究的目的是：(1)验证雄性和雌性大鼠随着年龄增长对NOS 3的调节存在差异的假设；(2)验证雄性大鼠氧化应激随年龄增长的指标出现的年龄比雌性大鼠早的假设。为了解决第一个目标，我们将检查内皮依赖性血管舒张和一氧化氮的生物利用度从衰老的雄性和雌性大鼠的阻力大小的动脉。我们将研究no3的调节是如何随着年龄的变化而改变的，以及这种影响是否具有性别特异性。为了解决第二个目标，我们将在年龄的进展中检查雄性和雌性大鼠的氧化应激指标。然后我们将确定年龄和性别对抗氧化系统的影响以及肠系膜血管中氧化应激的来源。

DESCRIPTION (provided by applicant): Advancing age and the male gender are risk factors for cardiovascular disease and are associated with vascular endothelium dysfunction. While the molecular mechanism mediating endothelial dysfunction has yet to be fully elucidated, it has been suggested to involve a decrease in nitric oxide (NO) bioavailability. A decline in NO may be due to (1) alterations in the activity/expression of the enzyme endothelial NO synthase (NOS 3), (2) alteration in NOS 3 substrate/cofactor availability, or (3) increased degradation of NO by superoxide. The rationale for this proposal is that a gender difference in the effects of age on NOS 3 regulation and NO bioavailability may contribute to the gender difference in endothelial dysfunction. The goal of this proposal is to examine how advancing age alters the NOS 3 system and oxidative stress in male and female rats. We hypothesize that with age there are alterations in NOS 3 regulation and increased oxidative stress resulting in decreased NO. In addition, we hypothesize that females will be "protected" from these effects of aging, such that males will experience a greater decline in NO compared to females. The aims of this proposal are to (1) test the hypothesis that male and female rats differentially regulate NOS 3 with advancing age, and (2) test the hypothesis that indicators of increased oxidative stress with age will appear in male rats at an earlier age compared to females. To address the first aim we will examine endothelium-dependent vasodilation and NO bioavailability in resistance-sized arteries from aging male and female rats. We will examine how NOS 3 regulation is altered with age, and if the effects are gender-specific. To address the second aim we will examine indicators of oxidative stress in male and female rats over a progression of ages. We will then determine the affects of age and gender on antioxidant systems and the sources of oxidative stress in the mesenteric vasculature.