Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes

被引:224
作者
Idris, I
Gray, S
Donnelly, R [1 ]
机构
[1] Univ Nottingham, Derbyshire Royal Infirm, Div Vasc Med, Jenny ONeil Diabet Ctr, Derby DE1 2QY, England
[2] Univ Nottingham, Sch Med & Surg Sci, Nottingham NG7 2RD, England
关键词
protein kinase C; PKC isoenzymes; insulin resistance; diacylglycerol; vascular complications; endothelial dysfunction; vascular permeability; PKC-beta PKC;
D O I
10.1007/s001250051675
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transduction and intracellular crosstalk by phosphorylating at serine/threonine residues an array of substrates, including cell-surface receptors, enzymes, contractile proteins, transcription factors and other kinases. Individual isozymes vary in their pattern of tissue and subcellular distribution, function and Ca2+/phospholipid cofactor requirements, and in diabetes there is widespread activation of the DAG-PKC pathway in metabolic, cardiovascular and renal tissues. In liver, muscle and adipose tissue, PKC isozymes have been implicated both as mediators and inhibitors of insulin action. Activation of DAG-sensitive PKC isoforms, such as PKC-theta and PKC-epsilon, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-zeta and PKC-lambda, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes. Glucose-induced de novo synthesis of (palmitate-rich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-beta) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription tin part by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e.g. vitamin E) and/or inhibit PKC isozymes (e.g. the beta -selective inhibitor LY333 531) ameliorate the biochemical and functional consequences of DAG-PKC activation in experimental diabetes, for example improving retinal blood flow and albuminuria in parallel with reductions in membrane-associated PKC isozyme activities. Thus, a greater understanding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits.
引用
收藏
页码:659 / 673
页数:15
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