Life and Death of Human Vascular Endothelial Cells by Stimulation with Free Fatty Acids Through Death Receptors

Abstract

Diabetic individuals may have elevated levels of serum free fatty acids and may exhibit injury to the vascular endothelial cells. This study was undertaken to determine the relationship between various free fatty acids (FFAs) and vascular endothelial cell injury and the molecular mechanisms linking FFA-induced vascular endothelial cells injury or protection. We observed the survival of HUVECs exposed to different FFAs, and our results revealed that the effects of various FFAs on the cell survival of HUVECs were significantly different. Palmitic acid (PA) markedly decreased the HUVEC survival rate in a time- and dose-dependent manner, but arachidonic acid (AA) significantly increased the cell survival rate and could partially prevent cellular apoptosis induced by PA. Interestingly, PA and AA could activate the same target receptor, TNF-R1. PA induced the apoptosis of HUVECs by initiating the death pathway (TNF-R1/TRADD/caspases 8 pathway), whereas AA enhanced cell survival to protect vascular endothelial cells by activating the survival pathway (TNF-R1/RIP/NF-κB 50/NF-κB 65).

Key words

free fatty acids - human umbilical vein endothelial cells - TNF-R1 - nuclear factor-kappa B - signaling pathways - arachidonic acid

^* These authors contributed equally to this study.

• References

• 1 McGarry JD. Review: Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002 51. 7-18
• 2 Chandie Shaw PK, Berger SP, Mallat M, Frölich M, Dekker FW, Rabelink TJ. Central obesity is an independent risk factor for albuminuria in nondiabetic South Asian subjects. Diabetes Care 2007; 30: 1840
• 3 Ruddock MW, Stein A, Landaker E, Park J, Cooksey RC, McClain D, Patti ME. Saturated fatty acids inhibit hepatic insulin action by modulating insulin receptor expression and post-receptor signaling. J Biochem 2008; 144: 599-607
• 4 Mu YM, Yanase T, Nishi Y, Tanaka A, Saito M, Jin CH, Mukasa C, Okabe T, Nomura M, Goto K, Nawata H. Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells. Endocrinology 2001; 142: 3590-3597
• 5 Cunha DA, Hekerman P, Ladrière L, Bazarra-Castro A, Ortis F, Wakeham MC, Moore F, Rasschaert J, Cardozo AK, Bellomo E, Overbergh L, Mathieu C, Lupi R, Hai T, Herchuelz A, Marchetti P, Rutter GA, Eizirik DL, Cnop M. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci 2008; 121 (Pt 14) 2308-2318
• 6 Chu KY, Lin Y, Hendel A, Kulpa JE, Brownsey RW, Johnson JD. ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic beta cells. J Biol Chem 2010; 285: 32606-32615
• 7 Tripathi AK, Sha W, Shulaev V, Stins MF, Sullivan Jr DJ. Plasmodium falciparum-infected erythrocytes induce NF-κB regulated inflammatory pathways in human cerebral endothelium. Blood 2009; 114: 4243-4252
• 8 Guicciardi ME, Gores GJ. Life and death by death receptors. FASEB J 2009; 23: 1625-1637
• 9 Sheikh MS, Huang Y. Death receptor activation complexes: it takes two to activate TNF receptor 1. Cell Cycle 2003; 2: 550-552
• 10 Liang GH, Park S, Kim JA, Choi S, Suh SH. Stimulation of large-conductance Ca²⁺-activated K⁺ channels by the Na⁺/Ca²⁺ exchanger inhibitor dichlorobenzamil in cultured human umbilical vein endothelial cells and mouse aortic smooth muscle cells. J Physiol Pharmacol 2009; 60: 43-50
• 11 Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat BI, Chi NW, Olefsky JM. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 2005; 280: 35361-35371
• 12 Green CJ, Macrae K, Fogarty S, Hardie DG, Sakamoto K, Hundal HS. Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase. Biochem J 2011; 435: 463-474
• 13 Yuan H, Zhang X, Huang X, Lu Y, Tang W, Man Y, Wang S, Xi J, Li J. NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways. PLoS One 2010; 5: 15726-15732
• 14 Shi Y. Caspase activation: revisiting the induced proximity model. Cell 2004; 117: 855-858
• 15 Tran SE, Holmstrom TH, Ahonen M, Kahari VM, Eriksson JE. MAPK/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors. J Biol Chem 2001; 276: 16484-16490
• 16 Kelley RF, Totpal K, Lindstrom SH, Mathieu M, Billeci K, Deforge L, Pai R, Hymowitz SG, Ashkenazi A. Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. J Biol Chem 2005; 280: 2205-2212
• 17 Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T. The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal 2010; 3 re4
• 18 Wang L, Du F, Wang X. TNF-α induces two distinct caspase-8 activation pathways. Cell 2008; 133: 693-703