Cilostazol Protects Endothelial Cells Against Lipopolysaccharide-Induced Apoptosis Through ERK1/2- and P38 MAPK-Dependent Pathways

Experimental studies have indicated that endothelial cells play an important role in maintaining vascular homeostasis. We previously reported that human coronary artery endothelial cells (HCAECs) express the glucagon-like peptide 1 (GLP1) receptor and that the stable GLP1 mimetic exendin-4 is able to activate the receptor, leading to increased cell proliferation. Here, we have studied the effect of exendin-4 and native GLP1 (7–36) on lipoapoptosis and its underlying mechanisms in HCAECs. Apoptosis was assessed by DNA fragmentation and caspase-3 activation, after incubating cells with palmitate. Nitric oxide (NO) and reactive oxidative species (ROS) were analyzed. GLP1 receptor activation, PKA-, PI3K/Akt-, eNOS-, p38 MAPK-, and JNK-dependent pathways, and genetic silencing of transfection of eNOS were also studied. Palmitate-induced apoptosis stimulated cells to release NO and ROS, concomitant with upregulation of eNOS, which required activation of p38 MAPK and JNK. Exendin-4 restored the imbalance between NO and ROS production in which ROS production decreased and NO production was further augmented. Incubation with exendin-4 and GLP1 (7–36) protected HCAECs against lipoapoptosis, an effect that was blocked by PKA, PI3K/Akt, eNOS, p38 MAPK, and JNK inhibitors. Genetic silencing of eNOS also abolished the anti-apoptotic effect afforded by exendin-4. Our results support the notion that GLP1 receptor agonists restore eNOS-induced ROS production due to lipotoxicity and that such agonists protect against lipoapoptosis through PKA-PI3K/Akt-eNOS-p38 MAPK-JNK-dependent pathways via a GLP1 receptor-dependent mechanism.

Download Full-text

Low level laser therapy prevent endothelial cells from TNF-alpha/cycloheximide-induced apoptosis by modulating P38 MAPK/NF-kB pathway

Physiotherapy ◽

10.1016/j.physio.2015.03.411 ◽

2015 ◽

Vol 101 ◽

pp. e236 ◽

Cited By ~ 2

Author(s):

Y.-J. Cheng ◽

H.-C. Ou ◽

C.-H. Lee

Keyword(s):

Endothelial Cells ◽

Laser Therapy ◽

P38 Mapk ◽

Low Level Laser Therapy ◽

Tnf Alpha ◽

Low Level ◽

Low Level Laser ◽

Level Laser ◽

Induced Apoptosis

Download Full-text

Heat stress prevents lipopolysaccharide-induced apoptosis in pulmonary microvascular endothelial cells by blocking calpain/p38 MAPK signalling

APOPTOSIS ◽

10.1007/s10495-016-1263-0 ◽

2016 ◽

Vol 21 (8) ◽

pp. 896-904 ◽

Cited By ~ 18

Author(s):

Zhi-feng Liu ◽

Dong Zheng ◽

Guo-chang Fan ◽

Tianqing Peng ◽

Lei Su

Keyword(s):

Endothelial Cells ◽

Heat Stress ◽

P38 Mapk ◽

Microvascular Endothelial Cells ◽

Pulmonary Microvascular Endothelial Cells ◽

Mapk Signalling ◽

Microvascular Endothelial ◽

Induced Apoptosis

Download Full-text

Ang (1–7) Protects Islet Endothelial Cells from Palmitate-Induced Apoptosis by AKT, eNOS, p38 MAPK, and JNK Pathways

Journal of Diabetes Research ◽

10.1155/2014/391476 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Li Yuan ◽

Chun-Li Lu ◽

Ying Wang ◽

Yang Li ◽

Xiao-Ya Li

Keyword(s):

Reactive Oxygen Species ◽

Endothelial Cells ◽

P38 Mapk ◽

Reactive Oxygen ◽

Treated Group ◽

Ros Production ◽

Oxygen Species ◽

Concomitant Reduction ◽

Jnk Inhibitors ◽

Induced Apoptosis

This study aimed to explore the effect of angiotensin (1–7) (Ang (1–7)) on palmitate-induced apoptosis in islet endothelial cells and the mechanism of action. MS-1 cells were treated with palmitate in the presence or absence of Ang (1–7). The percentage of apoptotic cells was determined by DNA fragmentation and flow cytometry. Reactive oxygen species (ROS) production was measured using a Reactive Oxygen Species Assay Kit. Expression of AKT, eNOS, C-Jun N-terminal kinase (JNK), and p38 was detected by western blotting. Compared with palmitate treated group, palmitate-induced apoptosis was decreased in MS-1 cells which were preincubated with Ang (1–7) (P<0.05). Palmitate decreased the phosphorylation of AKT and eNOS, and Ang (1–7) increased the phosphorylation of these kinases (P<0.05), with a concomitant reduction in MS-1 cells apoptosis. Ang (1–7) also inhibited the palmitate-induced ROS production and attenuated the apoptosis-related signaling molecule JNK and p38 activation (allP<0.05). PI3K/AKT, eNOS, p38 MAPK, and JNK inhibitors blocked the antilipoapoptosis of Ang (1–7) (allP<0.05). Our findings suggest that Ang (1–7) reduces palmitate-induced islet endothelial cells apoptosis. AKT/eNOS/NO signaling and JNK and p38 pathway are involved in the Ang (1–7)-mediated modulation of islet endothelial cells lipoapoptosis.

Download Full-text

p38 Mitogen-Activated Protein Kinase Mediates Palmitate-Induced Apoptosis But Not Inhibitor of Nuclear Factor-κB Degradation in Human Coronary Artery Endothelial Cells

Endocrinology ◽

10.1210/en.2006-1068 ◽

2007 ◽

Vol 148 (4) ◽

pp. 1622-1628 ◽

Cited By ~ 42

Author(s):

Weidong Chai ◽

Zhenqi Liu

Keyword(s):

Fatty Acids ◽

Endothelial Cells ◽

Coronary Artery ◽

P38 Mapk ◽

Fold Increase ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Human Coronary Artery ◽

Mapk Activity ◽

Induced Apoptosis

Plasma free fatty acids are elevated in patients with type 2 diabetes and contribute to the pathogenesis of insulin resistance and endothelial dysfunction. The p38 MAPK mediates stress, inflammation, and apoptosis. Whether free fatty acids induce apoptosis and/or activate nuclear factor-κB inflammatory pathway in human coronary artery endothelial cells (hCAECs) and, if so, whether this involves the p38 MAPK pathway is unknown. hCAECs (passages 4–6) were grown to 70% confluence and then incubated with palmitate at concentrations of 0–300 μm for 6–48 h. Palmitate at 100, 200, or 300 μm markedly increased apoptosis after 12 h of incubation. This apoptotic effect was time (P = 0.008) and dose (P = 0.006) dependent. Palmitate (100 μm for 24 h) induced a greater than 2-fold increase in apoptosis, which was accompanied with a 4-fold increase in p38 MAPK activity (P < 0.001). Palmitate did not affect the phosphorylation of Akt1 or ERK1/2. SB203580 (a specific inhibitor of p38 MAPK) alone did not affect cellular apoptosis; however, it abolished palmitate-induced apoptosis and p38 MAPK activation. Palmitate significantly reduced the level of inhibitor of nuclear factor-κB (IκB). However, treatment of cells with SB203580 did not restore IκB to baseline. We conclude that palmitate induces hCAEC apoptosis via a p38 MAPK-dependent mechanism and may participate in coronary endothelial injury in diabetes. However, palmitate-mediated IκB degradation in hCAECs is independent of p38 MAPK activity.

Download Full-text