Ca2+/calmodulin-dependent protein kinase- II in vasoactive peptide- induced responses and vascular biology.

Vasoactive peptides such as angiotensin II and endothelin-1 as well as growth factors regulate vascular homeostasis through signaling pathways that are triggered in both normal and disease states. These vasoactive peptides and growth factors also increase the cellular levels of calcium which, through calcium binding effector systems initiating the downstream signaling and physiological responses in target cells. A multifunctional calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as an important transducer of vasoactive peptide-induced responses in vascular smooth muscle cells (VSMC). The catalytic activity of CaMKII can be stimulated by autophosphorylation and oxidation leading to the activation of signaling events that mediate growth, proliferation, migration, and gene transcription in VSMC. Pharmacological and gene deletion approaches have demonstrated a requirement of CaMKII in mediating the mitogen- activated protein kinase and phosphatidyl-inositol 3-kinase/protein kinase B signalling, as well as the proliferative, migratory and transcriptional responses of vasoactive peptides. In addition, a potential involvement of hyperactive CaMKII in animal models of vascular disease has also been reported. Therefore, this review aims to highlight the role of CaMKII in mediating signaling and physiological responses in VSMC and discuss its potential role in vascular pathophysiology.

Involvement of the early growth response protein 1 in vascular pathophysiology: an overview.

Hyperactivation of proliferative and growth promoting pathways underlies the progression of vessel remodeling, leading to vascular dysfunction. An upregulation of early growth response protein 1 (Egr-1), a zinc finger transcription factor has been observed in several models of vascular diseases. In the vasculature, Egr-1 expression can be induced by multiple hormonal, metabolic and external stimuli, such as growth factors, cytokines, reactive oxygen species, hyperglycaemia and stretch-induced stress. The structure of the Egr-1 promoter allows both its auto-regulation and its binding with several regulatory transcription cofactors like the serum response factor and the cAMP response element binding protein. Pharmacological and genetic studies have revealed the involvement of several signaling pathways that contribute to the expression of Egr-1. Among them, the mitogen-activated protein kinase pathway has emerged as a predominant signaling cascade that regulates Egr-1 transcription in response to various stimuli. Moreover, targeted deletion of Egr-1 by DNAzymes, antisense oligonucleotides or RNA interference has also helped in defining the importance of Egr-1 in the pathophysiology of vascular diseases. Neointimal formation and expression of genes directly linked with proinflammatory processes have been demonstrated to be enhanced by Egr-1 expression and activity. This review provides an overview on the signaling components implicated in Egr-1 expression and discusses its potential involvement in vascular pathophysiology.