Saturated non-esterified fatty acids stimulate de novo diacylglycerol synthesis and protein kinase c activity in cultured aortic smooth muscle cells

Hai, Yu; Inoguchi, Toyoshi; Kakimoto, Maiko; Nakashima, Naoki; Imamura, Minako; Hashimoto, Toshihide; Umeda, Fumio; Nawata, Hajime

doi:10.1007/s001250051668

Cited by 52 publications

(30 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This result coincides with previous studies showing that saturated non-esterified fatty acids stimulate an increase in de novo intramuscular synthesis and accumulation of DAG [31,32] and the subsequent activation of PKCs [28][29][30][33][34][35] . Our results show that pre-treatment with wogonin significantly reduces the intracellular DAG levels and attenuates PKC phosphorylation (Figure 7).…”

Section: Discussionsupporting

confidence: 93%

“…Accumulating evidence suggests that the DAG/PKC pathway contributes to deleterious consequences in cells, including apoptosis in response to FFA administration [28][29][30][31][32][33][34][35] . Based on this evidence, we hypothesized that wogonin-mediated suppression of apoptosis might counter this mechanism and improve cell survival.…”

Section: Effects Of Wogonin On the Dag/pkc Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway

et al. 2011

View full text Add to dashboard Cite

Aim: To investigate the effects of wogonin (5,7-dihydroxy-8-methoxyflavone) extracted from Scutellaria baicalensis Georgi (S baicalensis) on lipotoxicity-induced apoptosis of vascular smooth muscle cells (VSMCs) and the underlying mechanisms. Methods: Cultured VSMCs were used. Apoptosis of VSMCs was induced by palmitate (0.75 mmol/L), and detected using TUNEL assay. The expression levels of protein and phosphorylated protein were measured using Western blot analysis. Results: Treatment of VSMCs with wogonin (10, 25 and 50 µmol/L) significantly attenuated the apoptosis and endoplasmic reticulum (ER) stress induced by palmitate in concentration-and time-dependent manners. Wogonin (50 µmol/L) decreased palmitate-induced reactive oxygen species (ROS) generation. The ER stress inhibitor 4-phenyl butyric acid (5 mmol/L) significantly decreased palmitateinduced apoptotic cells, and occluded the anti-apoptotic effect of wogonin (25 µmol/L). Wogonin (10, 25 and 50 µmol/L) significantly reduced the intracellular diacylglycerol (DAG) accumulation and expression levels of phosphorylated PKCs in palmitate-treated VSMCs. Conclusion: Our results suggest that wogonin inhibits lipotoxicity-induced apoptosis of VSMCs via suppressing the intracellular DAG accumulation and subsequent inhibition of PKC phosphorylation. Wogonin has therapeutic potential for the prevention and treatment of atherosclerosis.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Effects Of Wogonin On the Dag/pkc Pathwaymentioning

confidence: 99%

Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway

et al. 2011

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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)

show abstract

“…FFAs can increase the levels of diacylglycerol in cells to promote the activation of PKC (Yu et al 2001) and some fatty acids may also activate PKC more directly (Kasahara & Kikkawa 1995, Lu et al 2000. PKC is one of the isoforms of PKC that could be activated in fatty acid-treated cells, and this enzyme may be of particular importance for -cell lipotoxicity since it has been implicated as an inducer of apoptosis in a variety of cell types (Alcazar et al 1997, Carpenter et al 2002, Emoto et al 1995, Kikkawa et al 2002, Mizuno et al 1997, Niwa et al 2002.…”

Section: Introductionmentioning

confidence: 99%

Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells

Welters

Smith²,

Tadayyon³

et al. 2004

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Chronic exposure of pancreatic -cells to saturated fatty acids leads to loss of viability, an effect that has been implicated in the process of -cell 'lipotoxicity' associated with the progression of type 2 diabetes. The mechanisms involved are unknown but recent evidence has implicated the isoform of protein kinase C (PKC ) in mediating fatty acid toxicity. We have investigated this proposition in the clonal insulin-secreting cell line, BRIN-BD11. BRIN-BD11 cells were found to undergo apoptosis when exposed to palmitate and this response was attenuated by the purportedly selective inhibitor of PKC , rottlerin. However, activation of PKC with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), failed to promote cell death and down-regulation of PKC did not prevent the cytotoxic effects of palmitate. Moreover, rottlerin remained effective as a blocker of the palmitate response in cells depleted of PKC . Since rottlerin can inhibit various other kinases in addition to PKC , a range of additional kinase inhibitors was also tested. Of these, only the putative Ca 2+ /calmodulin-dependent protein kinase II (CaM kinase II) inhibitor, KN-62, was found to inhibit palmitate-induced cell death. However, this effect was not reproduced by a more selective pseudo-substrate inhibitor of CaM kinase II. Therefore, the present results reveal that palmitate induces cell death in BRIN-BD11 cells and suggest that this may involve the activation of a rottlerin (and KN-62)-sensitive kinase. However, it is clear that PKC is not required for this response.

show abstract

Saturated non-esterified fatty acids stimulate de novo diacylglycerol synthesis and protein kinase c activity in cultured aortic smooth muscle cells

Cited by 52 publications

References 16 publications

Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway

Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway

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

Evidence that protein kinase Cdelta is not required for palmitate-induced cytotoxicity in BRIN-BD11 beta-cells

Contact Info

Product

Resources

About