Regulating NOS2 in ischemic & post-ischemic myocardium

一氧化氮（NO）在心肌炎症性疾病中起重要作用。NO在病毒性心肌炎、移植排斥反应和心脏缺血后炎症中产生。心脏中NO的主要来源通常是内皮型一氧化氮合酶（eNOS或NOS3），它存在于内皮细胞、心肌细胞和血小板中。然而，心脏缺血或炎症时产生的细胞因子可诱导多种细胞（包括心肌细胞和巨噬细胞）表达诱导型NOS （iNOS或NOS2）。由于NOS2持续产生大量NO，与eNOS短暂产生少量NO相反，NOS2的表达改变了NO在心脏中的浓度和位置。NO产生的改变可能对心脏生理学有深远的影响，因为NO对心脏有多种影响，包括冠状动脉平滑肌的松弛，心肌细胞收缩性的抑制，血小板和白细胞粘附冠状动脉壁的减少，糖酵解和氧化磷酸化的抑制，以及凋亡途径的调节。由于NOS2衍生的NO可以影响心脏系统的多样性，因此NOS2的调控至关重要。虽然转录被认为是调控NOS2的主要机制，但也有其他机制调控NOS2的表达。我们的初步数据表明，新蛋白调节NOS2 mRNA的稳定性并调节NOS2蛋白的活性。我们建议研究NOS2调控的转录、转录后和翻译后机制。然后，我们将在心肌梗死缺血后模型中检查NOS2调节的生理相关性。这些研究将揭示缺血心肌中调节自由基产生的新机制。

Nitric oxide (NO) plays a major role in inflammatory diseases of the myocardium. NO is produced during viral myocarditis, transplant rejection, and post-ischemic inflammation in the heart. The major source of NO in the heart is normally endothelial nitric oxide synthase (eNOS or NOS3), which is present in endothelial cells, cardiac myocytes, and platelets. However, cytokines produced during ischemia or inflammation of the heart can induce expression of the inducible NOS (iNOS or NOS2) in a variety of cells, including cardiac myocytes and macrophages. Since NOS2 produces large amounts of NO continuously, in contrast to eNOS producing smaller amounts of NO transiently, the expression of NOS2 changes the concentration and location of NO in the heart. Alterations in NO production can have profound implications for cardiac physiology, since NO has a variety of effects upon the heart, including relaxation of coronary arterial smooth muscle, inhibition of cardiac myocyte contractility, reduction of platelet and leukocyte adhesion to the coronary artery wall, inhibition of glycolysis and oxidative phosphorylation, and regulation of apoptotic pathways. Because NO derived from NOS2 can affect a diversity of cardiac systems, the regulation of NOS2 is of critical importance. Although transcription was thought to be the primary mechanism by which NOS2 is regulated, other mechanisms regulate NOS2 expression as well. Our preliminary data show that novel proteins regulate the stability of NOS2 mRNA and regulate the activity of NOS2 protein. We propose to study transcriptional, post-transcriptional, and also post-translational mechanisms of NOS2 regulation. We then will examine the physiological relevance of NOS2 regulation in a post-ischemic model of myocardial infarction. These studies will characterize novel mechanisms which regulate radical production in ischemic myocardium.