Fatty acids modulate protein kinase C activation in porcine vascular smooth muscle cells independently of their effect on de novo diacylglycerol synthesis

Lu, Xiaolan; Yang, Xin; Howard, Randy L.; Walsh, James P.

doi:10.1007/s001250051504

Cited by 17 publications

(28 citation statements)

References 30 publications

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“…The absence of a change in total DAG effected by linoleate pre-treatment, despite elevation of TG, is counterintuitive, but consistent with previous work [31,32]. This and the fact that we were unable to show elevation of DAG in a specific compartment by subcellular fractionation suggests that the activation of nPKC isoforms is therefore likely to occur in response to elevation of minor polyunsaturated DAG species.…”

Section: Discussionsupporting

confidence: 91%

Dilinoleoyl-phosphatidic acid mediates reduced IRS-1 tyrosine phosphorylation in rat skeletal muscle cells and mouse muscle

et al. 2007

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Aims/hypothesis Insulin resistance in skeletal muscle is strongly associated with lipid oversupply, but the intracellular metabolites and underlying mechanisms are unclear. We therefore sought to identify the lipid intermediates through which the common unsaturated fatty acid linoleate causes defects in IRS-1 signalling in L6 myotubes and mouse skeletal muscle. Materials and methods Cells were pre-treated with 1 mmol/l linoleate for 24 h. Subsequent insulin-stimulated IRS-1 tyrosine phosphorylation and its association with the p85 subunit of phosphatidylinositol 3-kinase were determined by immunoblotting. Intracellular lipid species and protein kinase C activation were modulated by overexpression of diacylglycerol kinase ɛ, which preferentially converts unsaturated diacylglycerol into phosphatidic acid, or by inhibition of lysophosphatidic acid acyl transferase with lisofylline, which reduces phosphatidic acid synthesis. Phosphatidic acid species in linoleate-treated cells or muscle from insulin-resistant mice fed a safflower oil-based high-fat diet that was rich in linoleate were analysed by mass spectrometry. Results Linoleate pretreatment reduced IRS-1 tyrosine phosphorylation and p85 association. Overexpression of diacylglycerol kinase ɛ reversed the activation of protein kinase C isoforms by linoleate, but paradoxically further diminished IRS-1 tyrosine phosphorylation. Conversely, lisofylline treatment restored IRS-1 phosphorylation. Mass spectrometry indicated that the dilinoleoyl-phosphatidic acid content increased from undetectable levels to almost 20% of total phosphatidic acid in L6 cells and to 8% of total in the muscle of mice fed a high-fat diet. Micelles containing dilinoleoyl-phosphatidic acid specifically inhibited IRS-1 tyrosine phosphorylation and glycogen synthesis in L6 cells. Conclusions/interpretation These data indicate that linoleatederived phosphatidic acid is a novel lipid species that contributes independently of protein kinase C to IRS-1 signalling defects in muscle cells in response to lipid oversupply.

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Section: Discussionsupporting

confidence: 91%

Dilinoleoyl-phosphatidic acid mediates reduced IRS-1 tyrosine phosphorylation in rat skeletal muscle cells and mouse muscle

et al. 2007

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“…Multiple factors and their complex interactions may be involved in the regulatory pathway, and potential PKC regulators include DAG and other phospholipids, PDK (phosphoinositide-dependent kinase), RACKs (C kinase receptors), and tyrosine and serine/threonine kinases (29,30,32). Within this context, blood glucose is a potent stimulator of de novo synthesis of DAG and it also induces lipid synthesis and free fatty acid (FFA) production as indicated by a parallel increase in the levels of plasma FFA and blood glucose in diabetic patients (10,26,39). FFAs in turn further stimulate DAG synthesis (1,10,26,39,43) propagating the PKC signaling.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes

Guo

Korompai

et al. 2003

Physiological Genomics

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. Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes. Physiol Genomics 12: 139-146, 2003. First published November 19, 2002 10.1152/physiolgenomics.00125.2002The protein kinase C (PKC) pathway has recently been recognized as an important mechanism in the development of diabetic complications including cardiomyopathy and angiopathy. Although an increase in PKC kinase activity has been detected in the cardiovascular system of diabetic patients and animals, it is unclear whether the same pathological condition alters PKC at the transcriptional and translational levels. In this study we assessed quantitatively the mRNA and protein expression profiles of PKC isozymes in the heart and vascular tissues from streptozotocin-induced diabetic pigs. Partial regions of the porcine PKC␣, ␤1, and ␤2 mRNAs were sequenced, and real-time RT-PCR assays were developed for PKC mRNA quantification. The results showed a significant increase in the mRNA levels of PKC␣, ␤1, and ␤2 in the heart at 4-8 wk of diabetes. In concomitance, the PKC␤1 and ␤2 genes, but not the PKC␣ gene, were upregulated in the diabetic aorta. Correspondingly, there was a significant increase in the protein expression of PKC␣ and ␤2 in the heart and PKC␤2 in the aorta with a time course correlated to that of mRNA expression. In summary, PKC␤2 was significantly upregulated in the heart and aorta at both the transcriptional and translational levels during early stages of experimental diabetes, suggesting that PKC␤2 may be a prominent target of diabetic injury in the cardiovascular system. hyperglycemia; protein kinase C; gene and protein expression; real-time reverse transcription polymerase chain reaction DIABETES MELLITUS COMPRISES a host of pathological alterations characterized by multiple organ dysfunctions, of which the cardiovascular complications are the major cause of morbidity and mortality. Hyperglycemia is considered the primary etiological factor that initiates circulatory disorders such as cardiomyopathy, angiopathy, and atherosclerosis (15,28,38). Several hypotheses have been proposed to explain the adverse effects of elevated blood glucose, including the polyol pathway, nonenzymatic glycation, oxidative stress, and protein kinase C (PKC) activation (15,28,38). Of these mechanisms, activation of the PKC signaling pathway has been increasingly recognized as an early and common mechanism leading to cardiovascular dysfunction in hyperglycemia (11,15,16,18,35,38).The PKC family consists of multiple isoforms, categorized into the classic (e.g., ␣, ␤1, ␤2, and ␥), the novel (␦, ⑀, , , , and ), and the atypical ( and ) groups (8,28,38). These isozymes show distinct expression patterns and stimulate diverse cell responses (8,15,28,35,38). Among these isoforms, the classic group, especially PKC␣ and ␤, are better characterized, and their potential impacts on the cardiovascular system are emphasized (11, 14-16, 18-19, 25, 28, 38). For example, recent studies reveal a preferential increase of PKC␤ syn...

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“…OA is also incorporated into triglycerides (~35%), and causes a four-fold increase in total levels of triglycerides. However, the increase in triglycerides is unlikely to explain the mitogenic effects of OA because elaidic acid, a positional isomer of OA, results in similar increases in triglycerides [53] without affecting PDGF-BB-induced DNA synthesis. Instead, the mitogenic effect of OA appears to be dependent on PLD activity and conversion of phosphatidic acid to 1,2-DAG.…”

Section: Oa Could Mediate Its Mitogenic Effects By Causing Increased mentioning

confidence: 99%

“…Interestingly, it has been suggested that DAG species enriched in monounsaturated or unsaturated fatty acids act as better activators of protein kinase Cα than DAG species enriched in saturated fatty acids [58]. Accordingly, saturated fatty acids, such as palmitate and stearate, stimulate formation of DAG in SMCs [53,59], but do not enhance SMC proliferation. Thus, the results of our study strongly indicate that OA enhances the mi- Fig.…”

Section: Oa Could Mediate Its Mitogenic Effects By Causing Increased mentioning

confidence: 99%

Oleate, not ligands of the receptor for advanced glycation end-products, promotes proliferation of human arterial smooth muscle cells

et al. 2003

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Aims/hypothesis. Diabetes accelerates cardiovascular disease caused by atherosclerosis. Accordingly, diabetes accelerates atherosclerotic lesion progression and increases arterial smooth muscle cell proliferation. We hypothesized that diabetes can exert growth-promoting effects on smooth muscle cells via increased advanced glycation end-products or by dyslipidaemia. Methods. Primary human arterial smooth muscle cells were stimulated with advanced glycation end-products, other ligands of the receptor for advanced glycation end-products or fatty acids common in triglycerides. Cell proliferation was measured as DNA synthesis, cell cycle distribution and cell number. Effects of oleate on cellular phospholipids, diacylglycerol, triglycerides and cholesterol esters were analyzed by thin-layer chromatography, and oleate accumulation into diacylglycerol was confirmed by gas chromatography. Results. Human arterial smooth muscle cells express the receptor for advanced glycation end-products, but its ligands N ε -(carboxymethyl)lysine-modified proteins, methylglyoxal-modified proteins, S100B polypeptide and amyloid-β (1-40) peptide, exert no mitogenic action. Instead, oleate, one of the most common fatty acids in triglycerides, enhances platelet-derived growth factor-BB-mediated proliferation and oleate-containing 1,2-diacylglycerol formation in smooth muscle cells. This mitogenic effect of oleate depends on phospholipase D activity and is associated with an increased formation of oleate-enriched 1,2-diacylglycerol. Conclusion/interpretation. Oleate, not ligands of the receptor for advanced glycation end-products, acts as an enhancer of human smooth muscle cell proliferation. Thus, lipid abnormalities, rather than hyperglycaemia, could be a major factor promoting proliferation of smooth muscle cells in atherosclerotic lesions. [Diabetologia (2003[Diabetologia ( ) 46:1676[Diabetologia ( -1687 Keywords Atherosclerosis, diabetes, diacylglycerol, fatty acids, platelet-derived growth factor, phospholipase D, triglycerides. Atherosclerosis is accelerated by both Type I and Type 2 diabetes [1] by mechanisms that are poorly understood. Proliferation of arterial smooth muscle cells (SMCs) in lesions of atherosclerosis plays an important role in progression of early fatty streaks to fibroatheromas. We have recently reported that increased SMC proliferation in fibroatheromas occurs concomitantly with hyperglycaemia and an increased plasma triglyceride concentration in a porcine model of diabetes-accelerated atherosclerosis [2]. However, increased plasma glucose concentrations do not directly stimulate proliferation of SMCs isolated from these animals or from human subjects [2]. In this study, we investigated advanced glycation end-products (AGEs)

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Fatty acids modulate protein kinase C activation in porcine vascular smooth muscle cells independently of their effect on de novo diacylglycerol synthesis

Cited by 17 publications

References 30 publications

Dilinoleoyl-phosphatidic acid mediates reduced IRS-1 tyrosine phosphorylation in rat skeletal muscle cells and mouse muscle

Dilinoleoyl-phosphatidic acid mediates reduced IRS-1 tyrosine phosphorylation in rat skeletal muscle cells and mouse muscle

Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes

Oleate, not ligands of the receptor for advanced glycation end-products, promotes proliferation of human arterial smooth muscle cells

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