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In the past 10 years, an enormous amount of research has focused on the role of NAD(P)H oxidases in cardiovascular physiology and pathophysiology. Initially, investigators characterised these enzyme activities biochemically and functionally, but more recently, the molecular identification of a family of Nox (NADPH oxidase) proteins related to the respiratory burst NAD(P)H oxidase of neutrophils has led to an explosion of information about expression patterns, regulation, and functional significance of these enzyme complexes. Nox enzymes have been found to be involved in the regulation of vascular tone, smooth muscle growth, inflammatory responses, and matrix metalloproteinase activity. They have been implicated in hypertension, atherosclerosis, heart failure, diabetic vascular disease, and restenosis. In this article, the current status of the molecular basis for and the functional consequences of activation of these novel enzymes will be discussed.
NOX EXPRESSION IN THE CARDIOVASCULATURE
The first Nox enzyme to be cloned and characterised was termed gp91phox (or Nox2), because it is the catalytic unit of the phagocytic respiratory burst oxidase, which is important for non-specific host defence against invading microbes. This protein exists in a macromolecular complex with p22phox, another membrane subunit that stabilises gp91phox and interacts with the cytosolic regulatory factor p47phox. p47phox has two tandem SH3 groups that interact with auto-inhibitory domains to maintain the protein in an inactive state. Upon phosphorylation of p47phox by protein kinase C, this interaction is lost, and the SH3 groups and proline-rich tail are exposed and bind to the membrane subunits and a second regulatory cytosolic subunit, p67phox. p67phox, in turn, serves as a binding site for the small molecular weight G protein Rac, which modulates enzyme activity.1
Originally, gp91phox was thought to be restricted to phagocytic cells. Recent work, however, indicates that gp91phox is expressed at low, but functionally important levels in many tissues. More importantly, in …