Targeted delivery of small interfering RNA to angiogenic endothelial cells with liposome-polycation-DNA particles

Patients with type 2 diabetes are hyperinsulinemic and insulin resistant and develop premature atherosclerosis. High concentrations of insulin stimulate the production of adhesion molecules by endothelial cells (ECs). ECs express abundant IGF-I receptors as well as insulin receptors. Whether IGF-I receptors contribute to insulin-induced endothelial production of adhesion molecules is unknown. Bovine aortic ECs (BAECs) were incubated with insulin (100 nm) for 24 h. The cellular content of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was measured, and monocyte adhesion to ECs was quantified. Insulin increased both VCAM-1 (P < 0.001) and ICAM-1 (P < 0.0002) content, which was accompanied by an increased number of monocytes adherent to BAECs (P = 0.0001). Inhibition of either MAPK kinase-1 or p38 MAPK but not phosphatidylinositol 3-kinase abolished insulin-mediated production of adhesion molecules. Insulin receptor small interfering RNA knockdown abolished insulin-stimulated increases of ICAM-1 but not VCAM-1. Conversely, IGF-I receptor blockade with either a neutralizing antibody or specific small interfering RNA eliminated insulin-induced VCAM-1 but not ICAM-1 production. Blockade of signaling via either the insulin or IGF-I receptors decreased monocyte adherence to BAECs (P < 0.01 for each). We conclude that insulin and IGF-I receptors differentially mediate the production of adhesion molecules by ECs and monocyte adhesion onto the vascular endothelium in response to the hyperinsulinemic state. Dual-receptor activation may most effectively contribute to the pathogenesis of atherosclerotic disease in diabetes.

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Targeted Delivery of Small Interfering RNA Using Reconstituted High-Density Lipoprotein Nanoparticles

Neoplasia ◽

10.1593/neo.101372 ◽

2011 ◽

Vol 13 (4) ◽

pp. 309-IN8 ◽

Cited By ~ 137

Author(s):

Mian M.K. Shahzad ◽

Lingegowda S. Mangala ◽

Hee Dong Han ◽

Chunhua Lu ◽

Justin Bottsford-Miller ◽

...

Keyword(s):

High Density Lipoprotein ◽

Targeted Delivery ◽

Small Interfering Rna ◽

Density Lipoprotein ◽

High Density ◽

Interfering Rna

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CXCR4 down-regulation by small interfering RNA inhibits invasion and tubule formation of human retinal microvascular endothelial cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2007.05.004 ◽

2007 ◽

Vol 358 (4) ◽

pp. 990-996 ◽

Cited By ~ 9

Author(s):

Keming Yu ◽

Jing Zhuang ◽

Joseph M. Kaminski ◽

Bala Ambati ◽

Qianying Gao ◽

...

Keyword(s):

Endothelial Cells ◽

Small Interfering Rna ◽

Microvascular Endothelial Cells ◽

Down Regulation ◽

Tubule Formation ◽

Microvascular Endothelial ◽

Interfering Rna

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Targeted Delivery Systems of Small Interfering RNA by Systemic Administration

Drug Metabolism and Pharmacokinetics ◽

10.2133/dmpk.22.142 ◽

2007 ◽

Vol 22 (3) ◽

pp. 142-151 ◽

Cited By ~ 71

Author(s):

Shigeru Kawakami ◽

Mitsuru Hashida

Keyword(s):

Targeted Delivery ◽

Small Interfering Rna ◽

Delivery Systems ◽

Systemic Administration ◽

Interfering Rna ◽

Targeted Delivery Systems

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Reactive Nitrogen Species Induced by Hyperglycemia Suppresses Akt Signaling and Triggers Apoptosis by Upregulating Phosphatase PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) in an LKB1-Dependent Manner

Circulation ◽

10.1161/circulationaha.107.716498 ◽

2007 ◽

Vol 116 (14) ◽

pp. 1585-1595 ◽

Cited By ~ 112

Author(s):

Ping Song ◽

Yong Wu ◽

Jian Xu ◽

Zhonglin Xie ◽

Yunzhou Dong ◽

...

Keyword(s):

Endothelial Cells ◽

High Glucose ◽

Small Interfering Rna ◽

Umbilical Vein ◽

Akt Signaling ◽

Chromosome 10 ◽

Human Umbilical Vein ◽

Umbilical Vein Endothelial Cells ◽

Phosphatase And Tensin Homologue ◽

Interfering Rna

Background— Oxidative stress plays a causal role in vascular injury in diabetes mellitus, but the mechanisms and targets remain poorly understood. Methods and Results— Exposure of cultured human umbilical vein endothelial cells to either peroxynitrite (ONOO − ) or high glucose significantly inhibited both basal and insulin-stimulated Akt phosphorylation at Ser473 and Akt activity in parallel with increased apoptosis, phosphorylation, and activity of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Furthermore, protein kinase B/Akt inhibition induced by ONOO − or high glucose and apoptosis triggered by high glucose could be abolished by transfection of PTEN-specific small interfering RNA, suggesting that PTEN mediated the Akt inhibition by ONOO − . In addition, exposure of human umbilical vein endothelial cells to ONOO − or high glucose remarkably increased Ser428 phosphorylation of LKB1, a tumor suppressor. Interestingly, the ONOO − -enhanced PTEN phosphorylation and Akt inhibition can be blocked by LKB1-specific small interfering RNA. Consistently, LKB1 phosphorylated PTEN at Ser380/Thr382/383 in vitro, suggesting that LKB1 might act as an upstream kinase for PTEN. Compared with nondiabetic mice, the levels of PTEN, LKB1-Ser428 phosphorylation, and 3-nitrotyrosine (a biomarker of ONOO − ) were significantly increased in the aortas of streptozotocin-induced diabetic mice, which was in parallel with a reduction in Akt-Ser473 phosphorylation and an increase in apoptosis. Furthermore, administration of PTEN-specific small interfering RNA suppressed diabetes-enhanced apoptosis and Akt inhibition. Finally, treatment with Tempol, a superoxide dismutase mimetic, and insulin, both of which reduced the ONOO − formation, markedly reduced diabetes-enhanced LKB1-Ser428 phosphorylation, PTEN, and apoptosis in the endothelium of mouse aortas. Conclusion— We conclude that hyperglycemia triggers apoptosis by inhibiting Akt signaling via ONOO − -mediated LKB1-dependent PTEN activation.

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