PKCβ Promotes Vascular Inflammation and Acceleration of Atherosclerosis in Diabetic ApoE Null Mice

Abstract

Objective Diabetic subjects are at high risk for developing atherosclerosis through a variety of mechanisms. As the metabolism of glucose results in production of activators of protein kinase C (PKC)β, it was logical to investigate the role of PKCβ in modulation of atherosclerosis in diabetes. Approach and Results ApoE−/− and PKCβ −/−/ApoE−/− mice were rendered diabetic with streptozotocin. Quantification of atherosclerosis, gene expression profiling or analysis of signaling molecules was performed on aortic sinus or aortas from diabetic mice. Diabetes-accelerated atherosclerosis increased the level of phosphorylated ERK1/2 and JNK mitogen activated protein (MAP) kinases and augmented vascular expression of inflammatory mediators, as well as increased monocyte/macrophage infiltration and CD11c+ cells accumulation in diabetic ApoE−/− mice; processes which were diminished in diabetic PKCβ −/−/ApoE−/− mice. In addition, pharmacological inhibition of PKCβ reduced atherosclerotic lesion size in diabetic ApoE−/− mice. In vitro, the inhibitors of PKCβ and ERK1/2, as well as small interfering RNA (siRNA) to Egr-1 significantly decreased high glucose-induced expression of CD11c (Itgax), chemokine (C-C motif) ligand 2 (CCL2) and interleukin (IL)-1β in U937 macrophages. Conclusions These data link enhanced activation of PKCβ to accelerated diabetic atherosclerosis via a mechanism that includes modulation of gene transcription and signal transduction in the vascular wall; processes that contribute to acceleration of vascular inflammation and atherosclerosis in diabetes. Our results uncover a novel role for PKCβ in modulating CD11c expression and inflammatory response of macrophages in the development of diabetic atherosclerosis. These findings support PKCβ activation as a potential therapeutic target for prevention and treatment of diabetic atherosclerosis.

Pivotal Role of Serum- and Glucocorticoid-Inducible Kinase 1 in Vascular Inflammation and Atherogenesis

“…Because atherosclerosis is an inflammatory disease driven by over-recruitment of monocytes and monocyte-derived macrophages into an arterial lesion, macrophages are decisive for chronic vascular inflammation, which underlies the pathogenesis of atherosclerosis. 34,35 Beside monocyte recruitment, accumulation of monocytederived macrophages in atherosclerotic plaques depends on the balance between local proliferation and apoptosis as well as egress and clearance of apoptotic macrophages. 36,37 Although monocyte migration into plaques seems to be a major pathophysiological process in atherogenesis, 36 blunted accumulation of inflammatory cells and reduced plaque burden in sgk1 −/− mice could be influenced by further SGK1-dependent mechanisms involving modified migratory egress or apoptosis of macrophages.…”

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

“…In addition, complement mediated immunity activates PKC isoforms and triggers neurodegeneration during aging [65]. PKCβ accelerates inflammatory vascular disruption contributing to immune exhaustion [66]. What has yet to be fully elucidated is how age and co-morbidities alter PKC dynamics in diseases such as stroke and AD.…”

Old Suspect—New Evidence

“…In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kong et al 5 demonstrate that activated plasma membrane-bound PKCβ is elevated in the aortas of low dose streptozotocin-induced hyperglycemic Apoe −/− mice, and that PKCβ antagonism is sufficient to reduce accelerated atherosclerotic plaque burden in hyperglycemic Apoe −/− mice to levels comparable with the euglycemic Apoe −/− mice. Researchers have recognized the potential role of PKC isoforms and, particularly, PKCβ in diabetes mellitus and atherosclerosis for many years.…”

“…In the study by Kong et al, 5 the streptozotocin-treated Apoe −/− mouse model of diabetes mellitus provides an extreme condition of persistently elevated glucose exposure during atherogenesis. Additionally, although the authors maintain high levels of plasma glucose in streptozotocin-treated Apoe −/− mice during the development of atherosclerosis without any treatments, blood glucose levels are regulated in patients with diabetes mellitus.…”