Interaction of age and gender on NO bioavailability

描述（申请人提供）：年龄增长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，但已提出涉及一氧化氮（NO）生物利用度的降低。NO的下降可能是由于（1）内皮NO合酶（NOS 3）的活性/表达的改变，（2）NOS 3底物/辅因子可用性的改变，或（3）超氧化物对NO的降解增加。该建议的基本原理是年龄对NOS 3调节和NO生物利用度的影响的性别差异可能导致内皮功能障碍的性别差异。这项建议的目的是研究年龄的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，有改变NOS 3调节和增加氧化应激导致NO减少。此外，我们假设，女性将受到“保护”，从这些影响的老化，使男性将经历更大的下降NO相比，女性。本提案的目的是（1）检验雄性和雌性大鼠随着年龄的增长而差异调节NOS 3的假设，以及（2）检验雄性大鼠中随着年龄增长而增加的氧化应激指标将在比雌性大鼠更早的年龄出现的假设。为了解决第一个目标，我们将研究内皮依赖性血管舒张和NO生物利用度的阻力大小的动脉从老龄男性和女性大鼠。我们将研究NOS 3调节如何随年龄变化，以及这种影响是否具有性别特异性。为了解决第二个目标，我们将检查指标的氧化应激在雄性和雌性大鼠的年龄进展。然后，我们将确定年龄和性别对抗氧化系统的影响和肠系膜血管系统中氧化应激的来源。

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.