Transcriptional Activation by Hypoxia and Low-Density Lipoprotein Loading in Cultured Vascular Smooth Muscle Cells

Sugiyama, Akira; Wada, Youichiro; Izumi, Atsushi; Kobayashi, Mika; Kohro, Takahide; Patrick, C. Reid; Hamakubo, Takao; Kodama, Tatsuhiko

doi:10.5551/jat.e444

Cited by 3 publications

(5 citation statements)

References 27 publications

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“…The present study yielded similar results to a previous report that also examined leptin expression in HCASMCs subjected to hypoxia [ 23 ]. Under 2.5% O 2 hypoxia, significant oxidative stress induced hypoxic signaling (JNK) and activated leptin expression.…”

Section: Discussionsupporting

confidence: 92%

“…Its expression in increased by hypoxic conditions in various tissues such as placenta, pancreas, human skin dermal fibroblasts, adipocytes, and heart [ 4 , 19 - 22 ]. In fact, leptin is the gene most induced under hypoxia in human coronary arterial smooth muscle cell (HCASMC) [ 23 ]. Functional analyses of the leptin promoter reveal that hypoxic response elements mediate transcriptional activation by hypoxia.…”

Section: Introductionmentioning

confidence: 99%

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Molecular regulation of the expression of leptin by hypoxia in human coronary artery smooth muscle cells

2015

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BackgroundLeptin, produced mainly by white adipose tissue, is a hormone that promotes vascular smooth muscle cell (VSMC) migration and proliferation, a process involved in the pathophysiology of atherosclerosis. Leptin expression in human coronary artery smooth cell (HCASMC) is induced by hypoxia. However, our understanding of the process of atherosclerosis in HCASMC is only emerging. Since the mechanisms by which hypoxia regulates leptin in HCASMC are as yet unknown, this study aims to investigate the mechanics of molecular regulation of leptin expression in HCASMC under hypoxia. We subjected cultured HCASMCs to hypoxia for varying periods of time. Through use of different signal pathway inhibitors, we were able to sort out and identify the pathway through which hypoxia-induced leptin expression occurs.ResultsLeptin mRNA and protein levels increased after 2.5% hypoxia for 2-to-4 hours, with earlier expression of angiotensin II (AngII) and reactive oxygen species (ROS). The addition before hypoxia of the c-Jun N-terminal kinase (JNK) pathway inhibitor (SP600125), JNK small interfering RNA (siRNA), AngII receptor blockers (ARBs; losartan), or N-acetyl-L-cysteine (NAC, an ROS scavenger), had the effect of inhibiting JNK phosphorylation and leptin expression. Gel shift assay and luciferase promoter study showed that leptin/activator protein 1 (AP-1) binding and transcriptional activity to the leptin promoter increased after hypoxia, and SP600125, JNK siRNA, losartan, and NAC abolished the binding and transcriptional activity induced by hypoxia. The use of SP600125, JNK siRNA, losartan, and NAC effectively inhibited the binding and transcriptional activity induced by hypoxia. Migration and proliferation, ROS generation, and the presence of leptin in the nuclei of HCASMCs also increased under hypoxia.ConclusionHypoxia in HCASMCs increases leptin expression through the induction of AngII, ROS, and the JNK pathway to enhance atherosclerosis in HCASMCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-014-0109-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Molecular regulation of the expression of leptin by hypoxia in human coronary artery smooth muscle cells

2015

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“…Leptin is considered to be a specific adipocyte product. Recent reports [9,10] and our present study have shown leptin production by non-adipose cells. Leptin production by VSMCs was not widely investigated.…”

Section: Discussionmentioning

confidence: 49%

“…Leptin production by VSMCs was not widely investigated. Sugiyama et al [10] have reported that a combination of hypoxia and high low-density lipoprotein level conditions induced leptin expression in HCASMCs. Our study is the first one to investigate VSMC leptin in detail.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, Bodary et al [8] have shown that direct administration of leptin in apolipoprotein E-deficient mice results in increased atherosclerosis. Recent reports have shown leptin production by non-adipose cells, such as vascular endothelial cells and SMCs (smooth muscle cells) [9,10], indicating that leptin may be an inducible, locally produced, proatherogenic mediator.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of the inhibitory effect of atorvastatin on leptin expression induced by angiotensin II in cultured human coronary artery smooth muscle cells

Shyu

Chen

Wang³

et al. 2011

Clinical Science

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Leptin contributes to the pathogenesis of atherosclerosis. Ang II (angiotensin II), a proatherogenic cytokine, increases leptin synthesis in cultured adipocytes. Statin suppresses leptin expression in adipocytes and human coronary artery endothelial cells. However, the effect of Ang II and statin on leptin expression in VSMCs (vascular smooth muscle cells), the major cell types in atheroma, is poorly understood. Thus the aim of the present study was to investigate the molecular mechanism of atorvastatin for reducing leptin expression after Ang II stimulation in VSMCs. VSMCs from human coronary artery were cultured. Ang II stimulation increased leptin protein and mRNA and phospho-JNK (c-Jun N-terminal kinase) expression. Exogenous addition of Dp44mT (2,2'-dipyridyl-N,N-dimethylsemicarbazone) and mevalonate increased leptin protein expression similarly to Ang II. Atorvastatin, SP600125, JNK siRNA (small interfering RNA) and NAC (N-acetylcysteine) completely attenuated the leptin and phospho-JNK protein expression induced by Ang II. Ang II significantly increased ROS (reactive oxygen species) formation in human VSMCs. Addition of atorvastatin and NAC significantly attenuated the formation of ROS induced by Ang II. Addition of atorvastatin and SP600125 inhibited the phosphorylation of Rac1 induced by Ang II. The gel shift and promoter activity assay showed that Ang II increased AP-1 (activator protein-1)-binding activity and leptin promoter activity, while SP600125, NAC and atorvastatin inhibited the AP-1-binding activity and leptin promoter activity induced by Ang II. Ang II significantly increased the migration and proliferation of cultured VSMCs, while addition of atorvastatin, SP600125, NAC and leptin siRNA before Ang II stimulation significantly inhibited the migration and proliferation of VSMCs induced by Ang II. Ang II significantly increased secretion of leptin from human VSMCs, and addition of SP600125, atorvastatin and NAC before Ang II stimulation almost completely inhibited the leptin secretion induced by Ang II. In conclusion, Ang II induces leptin expression in human VSMCs, and atorvastatin could inhibit the leptin expression induced by Ang II. The inhibitory effect of atorvastatin on Ang II-induced leptin expression was mediated by Rac, ROS and JNK pathways.

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Current World Literature

2008

Current Opinion in Lipidology

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Transcriptional Activation by Hypoxia and Low-Density Lipoprotein Loading in Cultured Vascular Smooth Muscle Cells

Cited by 3 publications

References 27 publications

Molecular regulation of the expression of leptin by hypoxia in human coronary artery smooth muscle cells

Molecular regulation of the expression of leptin by hypoxia in human coronary artery smooth muscle cells

Mechanism of the inhibitory effect of atorvastatin on leptin expression induced by angiotensin II in cultured human coronary artery smooth muscle cells

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