Dept. of Chemistry and Physical Sciences, Pace Univ., One Pace Plaza, New York, NY 10038, USA.
Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H617-24. doi: 10.1152/ajpheart.00667.2010. Epub 2011 May 20.
Nitric oxide (NO) is an important vasoactive molecule produced by three NO synthase (NOS) enzymes: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). While eNOS contributes to blood vessel dilation that protects against the development of hypertension, iNOS has been primarily implicated as a disease-promoting isoform during atherogenesis. Despite this, iNOS may play a physiological role via the modulation of cyclooxygenase and thromboregulatory eicosanoid production. Herein, we examined the role of iNOS in a murine model of thrombosis. Blood flow was measured in carotid arteries of male and female wild-type (WT) and iNOS-deficient mice following ferric chloride-induced thrombosis. Female WT mice were more resistant to thrombotic occlusion than male counterparts but became more susceptible upon iNOS deletion. In contrast, male mice (with and without iNOS deletion) were equally susceptible to thrombosis. Deletion of iNOS was not associated with a change in the balance of thromboxane A(2) (TxA(2)) or antithrombotic prostacyclin (PGI(2)). Compared with male counterparts, female WT mice exhibited increased urinary nitrite and nitrate levels and enhanced ex vivo induction of iNOS in hearts and aortas. Our findings suggest that iNOS-derived NO in female WT mice may attenuate the effects of vascular injury. Thus, although iNOS is detrimental during atherogenesis, physiological iNOS levels may contribute to providing protection against thrombotic occlusion, a phenomenon that may be enhanced in female mice.
一氧化氮（NO）是一种重要的血管活性分子，由三种一氧化氮合酶（NOS）酶产生：神经元型（nNOS）、诱导型（iNOS）和内皮型 NOS（eNOS）。虽然 eNOS 有助于血管扩张，从而防止高血压的发展，但 iNOS 主要被认为是动脉粥样硬化形成过程中的一种促进疾病的同工酶。尽管如此，iNOS 可能通过调节环氧化酶和血栓调节性花生四烯酸的产生来发挥生理作用。在此，我们研究了 iNOS 在血栓形成的小鼠模型中的作用。在雄性和雌性野生型（WT）和 iNOS 缺陷型小鼠的颈总动脉中，通过三氯化铁诱导的血栓形成来测量血流。雌性 WT 小鼠对血栓闭塞的抵抗力强于雄性，但在 iNOS 缺失后变得更易受影响。相比之下，雄性小鼠（无论是否缺失 iNOS）对血栓形成的敏感性相同。iNOS 的缺失与血栓烷 A2（TxA2）或抗血栓前列环素（PGI2）的平衡变化无关。与雄性相比，雌性 WT 小鼠的尿亚硝酸盐和硝酸盐水平升高，并且在心脏和主动脉中诱导 iNOS 的体外活性增强。我们的研究结果表明，雌性 WT 小鼠中 iNOS 衍生的 NO 可能会减弱血管损伤的影响。因此，尽管 iNOS 在动脉粥样硬化形成过程中有害，但生理水平的 iNOS 可能有助于提供对血栓闭塞的保护，这种现象在雌性小鼠中可能会增强。
