Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases.
Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as postangioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and reactive nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing coexpression of iNOS and Nox in vascular smooth muscle demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen-activated protein kinases are important modulators of proinflammatory cytokine-dependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cdelta is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of nonphagocytic NADPH oxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merits further investigation.
Ginnan
Roman
R
Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.
Guikema
Benjamin J
BJ
Halligan
Katharine E
KE
Singer
Harold A
HA
Jourd'heuil
David
D
D000818:Animals; D049109:Cell Proliferation; D005609:Free Radicals; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism / Q000502:physiology*; D010587:Phagocytosis; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species; D014652:Vascular Diseases / Q000473:pathology*
D005609:Free Radicals; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D011493:Protein Kinase C