Abstract
Diabetes mellitus is a metabolic syndrome that affects millions of people worldwide. Recent studies have demonstrated that protein kinase C (PKC) activation plays an important role in hyperglycemia-induced atherosclerosis. PKC activation is involved in several cellular responses such as the expression of various growth factors, activation of signaling pathways, and enhancement of oxidative stress in hyperglycemia. However, the role of PKC activation in pro-atherogenic and anti-atherogenic mechanisms remains controversial, especially under hyperglycemic condition. In this review, we discuss the role of different PKC isoforms in lipid regulation, oxidative stress, inflammatory response, and apoptosis. These intracellular events are linked to the pathogenesis of atherosclerosis in diabetes. PKC deletion or treatment with PKC inhibitors has been studied in the regulation of atherosclerotic plaque formation and evolution. Furthermore, some preclinical and clinical studies have indicated that PKCβ and PKCδ are potential targets for the treatment of diabetic vascular complications. The current review summarizes these multiple signaling pathways and cellular responses regulated by PKC activation and the potential therapeutic targets of PKC in diabetic complications.
Highlights
Diabetes mellitus (DM), a highly prevalent disease worldwide, is caused by insufficient insulin production or insulin resistance
We previously demonstrated that knockdown of PKCδ by shRNA or siRNA effectively reduced scavenger receptor A (SR-A), CD36 expression, oxidize LDL (oxLDL) uptake, and foam cell formation through PI3K/Akt and extracellular signalregulated kinase (ERK) signaling pathways in THP-1derived macrophages and human primary macrophages (Lin et al, 2012)
A previous study indicated that inhibition of hepatic insulin receptor reduces LDL receptor (LDLR) protein expression, which is possibly due to upregulating the levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) via hepatic mTOR1 mediated PKCδ pathway (Ai et al, 2012)
Summary
Diabetes mellitus (DM), a highly prevalent disease worldwide, is caused by insufficient insulin production or insulin resistance. These studies suggest that PKC isoforms, namely PKCα, PKCβ, PKCε, and PKCδ, contribute to cholesterol regulation in hepatocytes. LDLR, low density lipoprotein receptor; AS, antisense oligonucleotide; HUVECs, human umbilical vein endothelial cells; ICAM-1, intercellular cell adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; CCR2, C-C chemokine receptor type 2; CXCL2, C-X-C Motif Chemokine Ligand 2; HAECs, human aortic endothelial cells; MMP, matrix metalloproteinase; ABCA1, ATP binding cassette subfamily A member 1; ABCG1, ATP binding cassette subfamily G member 1; HFD, High-fat diet; BMDMs, bone marrow-derived macrophages; PBMC, peripheral blood mononuclear cell; HMDMs, human monocyte-derive macrophages; HCAECs, human coronary artery endothelial cells; PDGF, platelet-derived growth factor; DN, dominant negative; Tg, transgenic inhibition; ROS, Reactive oxygen species; PKC, protein kinase C; IL, interleukin; Ang II, Angiotensin II, RBX, ruboxistaurin.
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