Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology

Emerging evidence indicates that reactive oxygen species, especially supero xide and hydrogen peroxide, are important signaling molecules in cardiovasc ular cells. Their production is regulated by hormone-sensitive enzymes such as the vascular NAD(P)H oxidases, and their metabolism is coordinated by a ntioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Both of these reactive oxygen species serve as second messenger s to activate multiple intracellular proteins and enzymes, including the ep idermal growth factor receptor, c-Src, p38 mitogen-activated protein kinase , Ras, and Akt/protein kinase B. Activation of these signaling cascades and redox-sensitive transcription factors leads to induction of many genes wit h important functional roles in the physiology and pathophysiology of vascu lar cells. Thus, reactive oxygen species participate in vascular smooth mus cle cell growth and migration; modulation of endothelial function, includin g endothelium-dependent relaxation and expression of a proinflammatory phen otype; and modification of the extracellular matrix. All of these events pl ay important roles in vascular diseases such as hypertension and atheroscle rosis, suggesting that the sources of reactive oxygen species and the signa ling pathways that they modify may represent important therapeutic targets.