PKCδ signalling regulates SR-A and CD36 expression and foam cell formation

Lin, Chin; Lin, Feng Yen; Ho, Ling Jun; Tsai, Chien‐Sung; Cheng, Shu Mung; Wu, Wen-Chung; Huang, Ching-Yu; Lian, Chen Hao; Yang, Sung‐Pei; Lai, Jenn Haung

doi:10.1093/cvr/cvs189

Cited by 56 publications

(41 citation statements)

References 30 publications

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“…11,[13][14][15] Several lines of evidence have shown that foam cell formation and CD36 and ACAT1 expression in macrophages and the migration and proliferation of VSMCs are mediated via ERK-1/2. 19,20,28,38 The results from the present study suggest that CT-1 induces VSMC proliferation via the CT-1 receptor, ERK-1/2, Janus kinase/signal transducer and activation of transcription-3, and NF-κB pathways, and upregulates CD36 and ACAT1 expression via the CT-1 receptor, phosphatidylinositol-3 kinase, Akt1/2, and ERK-1/2 pathways in macrophages.…”

Section: Discussionsupporting

confidence: 50%

Stimulatory Effects of Cardiotrophin 1 on Atherosclerosis

Konii

Sato²,

Kikuchi³

et al. 2013

Hypertension

109

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A therosclerosis is a pathological injury-to-response process that is initiated by early inflammatory responses of vascular endothelial cells (ECs).1 Endothelial inflammation is characterized by increased production of proatherogenic molecules and inflammatory cytokines in ECs, and monocyte adhesion and infiltration into the neointima lesion, followed by oxidized low-density lipoprotein-induced transformation of macrophages into foam cells.2 Accumulation of cholesterol ester in macrophages is a hallmark of foam cell formation. 2This accumulation depends on the balance between the uptake of oxidized low-density lipoprotein via CD36 and the efflux of free cholesterol controlled by ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1, or scavenger receptor class B type I (SR-BI).3 To protect the cells from the toxicity that would result from excessive free cholesterol accumulation, the free cholesterol is esterified to cholesterol ester by acyl-CoA:cholesterol acyltransferase-1 (ACAT1).3 Cholesterol ester stored in lipid droplets can be removed from cells only after hydrolysis to free cholesterol by neutral cholesterol ester hydrolase. 4 Apart from accumulation of macrophage-derived foam cells, the migration and proliferation of vascular smooth muscle cells (VSMCs) followed by extracellular matrix (ECM) production play crucial roles in the development of atherosclerotic lesions. 1Cardiotrophin 1 (CT-1), a 201-aa member of the interleukin-6 cytokine family, was originally cloned from embryoid bodies as a 21.5-kDa protein capable of inducing hypertrophy in neonatal cardiomyocytes. 5 Human and mouse CT-1 share 80% amino acid sequence identity and exhibit cross-species activity.6 Subsequent studies confirmed that plasma concentrations of CT-1 are elevated in various cardiorenal diseases, such as hypertension, ischemic heart disease, heart failure, and chronic renal disease.7-10 CT-1 exerts cardiovascular remodeling induced by hypertensive and ischemic heart diseases and congestive heart failure, through its receptor complex glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR).11-14 Recently, CT-1 has been shown to be expressed in the intima in the early stages of atherosclerotic lesions in human carotid artery.15 CT-1 stimulates the synthesis of inflammatory cytokines and proatherogenic molecules, such as interleukin-6, Abstract-Cardiotrophin 1 (CT-1), an interleukin-6 family cytokine, was recently shown to be expressed in the intima of early atherosclerotic lesions in the human carotid artery. CT-1 stimulates proatherogenic molecule expression in human vascular endothelial cells and monocyte migration. However, it has not been reported whether CT-1 accelerates atherosclerosis. This study was performed to examine the stimulatory effects of CT-1 on human macrophage foam cell formation and vascular smooth muscle cell migration and proliferation in vitro, and on the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE −/− ) mice in vivo. CT-1 was express...

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Section: Discussionsupporting

confidence: 50%

Stimulatory Effects of Cardiotrophin 1 on Atherosclerosis

Konii

Sato²,

Kikuchi³

et al. 2013

Hypertension

109

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“…Selective inhibition of PI3K/Akt/mTOR signaling pathway can reduce macrophages and stabilize the atherosclerotic plaques by promoting macrophage autophagy, 268 through affect atherosclerotic plaque inflammation, burden and vulnerability both in vitro and in vivo [31] . In this study, we found that Akt phosphorylation significantly decreased when the plasma H 2 S level <13.45 μmol/l; this suggested that the cPKCβII/Akt activation may involve in the cardiovascular protective function of H 2 S. Although an interaction between PKC and Akt in human vascular endothelial cells and atherogenesis formation has been demonstrated [32,33] , and the neuroprotective effect of H 2 S involved the PKC-dependent PI3K/Akt pathway is confirmed in human neuroblastoma SH-SY5Y cell line [12] , the activation sequence between PKC and PI3K/Akt has not been fully elucidated. Accordingly, our study has certified the activation of cPKCβII and inactivation of Akt in hemodialysis patients with plasma H 2 S levels <13.45 μmol/l, but the activation sequence and mechanism need to be further investigated.…”

Section: Discussionmentioning

confidence: 70%

Lower Hydrogen Sulfide Is Associated with Cardiovascular Mortality, Which Involves cPKCβII/Akt Pathway in Chronic Hemodialysis Patients

Feng

Wang³

2015

Blood Purif

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Background/Aims: To evaluate the relationship between plasma hydrogen sulfide (H₂S) and cardiovascular risk markers, including pulse pressure (PP), left ventricular mass index (LVMI) and intima-media thickness (IMT), and mortality in chronic hemodialysis (CHD) patients and further investigate the underlying cardiovascular protection mechanism of H₂S. Methods: CHD patients, 113 of them, were studied. Plasma H₂S was measured through zinc acetate reaction. cPKCβII membrane translocation and phosphorylation of Akt were detected by western blot. Results: Lower plasma H₂S level in CHD patients was predictor of an increased PP, LVMI and IMT. Patients with lower H₂S had a lower survival at the end of the study. H₂S was an independent predictor of all-cause and cardiovascular mortality when adjusted for other risk factors. CHD patients with lower H₂S showed an increase of cPKCβII activation, but phosphorylation of Akt decreased. The level of VCAM-1 and ICAM-1 increased significantly. Conclusions: Lower plasma H₂S in CHD patients is associated with cardiovascular risk factors and mortality, which may be mediated by the cPKCβII/Akt pathway and further VCAM-1/ICAM-1 upregulation.

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“…It is known that oxLDLs (and HIV protease inhibitors) induce CD36 expression by increasing ROS production and activating PKC␦ (6,10,15,29). To determine whether nicotine also activates the PKC pathway, we measured PKC␦ and phospho-PKC␦ expression in THP1 macrophages after nicotine stimulation.…”

Section: Cd14mentioning

confidence: 99%

Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling

Zhou

Chadipiralla

Mendez

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Zhou MS, Chadipiralla K, Mendez AJ, Jaimes EA, Silverstein RL, Webster K, Raij L. Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling. Am J Physiol Heart Circ Physiol 305: H563-H574, 2013. First published June 7, 2013 doi:10.1152/ajpheart.00042.2013.-Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36 ϩ /CD14 ϩ cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKC␦ phosphorylation, and peroxisome proliferator-activated receptor-␥ (PPAR␥) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKC␦ and PPAR␥ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-␣, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 g/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE Ϫ/Ϫ mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36 Ϫ/Ϫ apoE Ϫ/Ϫ mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use of high concentrations of nicotine independent of their mode of administration.nicotine; CD36; inflammatory cytokine; macrophage; foam cell SMOKING ACCOUNTS FOR 175,000 cardiovascular (CV) deaths annually in the US. The range of CV diseases exacerbated by cigarette smoke includes diabetic and obesity-related vascular diseases, stroke, myocardial infarction, peripheral vascular, and renal disease (20,35,50). Heart attacks are three times more common in smokers than in nonsmokers, and it is estimated that ϳ30% of deaths from coronary heart disease in the US are attributable to smoking (35). We and others (16,18) have demonstrated the importance of chemically stable compounds present in the gas phase of cigarette smoke in mediating endothelial injury and a...

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PKCδ signalling regulates SR-A and CD36 expression and foam cell formation

Cited by 56 publications

References 30 publications

Stimulatory Effects of Cardiotrophin 1 on Atherosclerosis

Stimulatory Effects of Cardiotrophin 1 on Atherosclerosis

Lower Hydrogen Sulfide Is Associated with Cardiovascular Mortality, Which Involves cPKCβII/Akt Pathway in Chronic Hemodialysis Patients

Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling

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