Proatherosclerotic Mechanisms Involving Protein Kinase C in Diabetes and Insulin Resistance

Abstract

Abstract-In diabetes and insulin resistance, activation of protein kinase C (PKC) in vascular cells may be a key linkbetween elevated plasma and tissue concentrations of glucose and nonesterified fatty acids and abnormal vascular cell signaling. Initial studies of PKC activation in diabetes focused on microvascular complications, but increasing evidence supports that PKC plays a role in several mechanisms promoting atherosclerosis. This review explains how PKC is thought to be activated in diabetes and insulin resistance through de novo synthesis of diacylglycerol. Furthermore, the review summarizes studies that implicate PKC in promoting proatherogenic mechanisms or inhibiting antiatherogenic mechanisms, including studies of endothelial dysfunction; gene induction and activation of vascular NAD(P)H oxidase; endothelial nitric oxide synthase expression and function; endothelin-1 expression; growth, migration, and apoptosis of vascular smooth muscle cells; induction of adhesion molecules; and oxidized low-density lipoprotein uptake by monocyte-derived macrophages.

Mechanisms by which diabetes increases cardiovascular disease

“…Although the role of scavenger receptors in atherogenesis is controversial [19], induction of scavenger receptor class A and CD36 in macrophages due to AGE may represent another pro-atherogenic mechanism [17]. In summary, AGE formation due to hyperglycemia may promote development of atherosclerotic lesions by various well-known pro-atherogenic receptors [20].…”

“…Adhesion of human monocytes to HUVEC is promoted by oxLDL and can be blocked by pretreating monocytes with PKC-inhibitors [20]. Many adhesion molecules are induced in endothelial cells by hyperglycemias, specifically PKCδ has been demonstrated to mediate thrombin-induced ICAM-1 expression in HUVEC [20].…”

“…Many adhesion molecules are induced in endothelial cells by hyperglycemias, specifically PKCδ has been demonstrated to mediate thrombin-induced ICAM-1 expression in HUVEC [20]. Glucose itself also increases monocyte adhesion to the endothelium [27].…”

“…Glucose itself also increases monocyte adhesion to the endothelium [27]. Glucose-induced expression of the scavenger receptor LOX-1 in macrophages can be inhibited by treatment with a PKCβ inhibitor [20]. Similarly, glucose-induced proliferation of rat vascular smooth muscle cells is mediated by PKCα through induction of transforming growth factor (TGF)-β, an effect that is inhibited by either antisense oligonucleotides or pharmacological inhibition [20].…”

“…Many different PKC inhibitors have been used in vitro [20]. Ruboxistaurin, a PKCβ-specific inhibitor, has been in clinical development for microvascular disease but results have not been definitive enough to recommend approval at this stage [6].…”