Leptin Stimulated C-Reactive Protein Production by Human Coronary Artery Endothelial Cells

Rosa, Salvatore De; Cirillo, Plinio; Pacileo, Mario; Palma, V.; Paglia, Antonella; Chiariello, Massimo

doi:10.1159/000226229

Cited by 54 publications

(43 citation statements)

References 70 publications

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“…Pulmonary vascular production of CRP In agreement with previous findings reporting that vascular SMCs are the major source of CRP local production in systemic injured or atherosclerotic arteries [38] and that vascular ECs may also produce CRP [39], this is the first study to report a local production of CRP by ECs and SMCs in CTEPH proximal pulmonary arterial tissue. This locally produced CRP might contribute to endothelial dysfunction, vascular remodelling and in situ thrombosis in CTEPH ( fig.…”

Section: In Vitro Effects Of Crp On Pulmonary Vascular Cellssupporting

confidence: 90%

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

et al. 2012

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Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by proximal pulmonary vascular obstruction by thrombo-fibrotic material, the origin of which has not been elucidated. Enhanced inflammation could contribute to persistent obstruction by impairing pulmonary vascular cell function in CTEPH. We investigated C-reactive protein (CRP) effects on pulmonary vascular cell function in vitro.Primary cultures of proximal pulmonary endothelial cells (ECs) and smooth muscle cells (SMCs) from CTEPH and nonthromboembolic pulmonary hypertension (PH) patients were established. Recombinant CRP effects on mitogenic activity, adhesion capacity, endothelin-1 and von Willebrand factor (vWF) secretion and intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1 expression were investigated in ECs and/or SMCs. Expression of the CRP receptor, lectin-like oxidised low-density lipoprotein receptor (LOX)-1, was evaluated in proximal pulmonary arterial tissue and cells by Western blotting and immunofluorescence.CRP increased CTEPH-SMC proliferation by 250%. CRP increased adhesion capacity, endothelin-1 and vWF secretion by CTEPH-ECs by 37%, 129% and 694%, respectively. CRP-induced adhesion of CTEPH-ECs to monocytes was mediated by ICAM-1. CRP had no effect on cells from nonthromboembolic PH patients, probably because of overexpression of LOX-1 in CTEPH. Local expression of CRP was detected in ECs and SMCs within pulmonary arterial tissue.CRP may contribute to persistent obstruction of proximal pulmonary arteries in CTEPH by promoting vascular remodelling, endothelial dysfunction and in situ thrombosis. KEYWORDS: C-reactive protein, chronic thromboembolic pulmonary hypertension, endothelial cells, inflammation, smooth muscle cells C hronic thromboembolic pulmonary hypertension (CTEPH) is one of the main causes of severe pulmonary hypertension. CTEPH is characterised by intraluminal thrombus organisation and fibrous stenosis or complete obliteration of proximal pulmonary arteries. The consequence is an increased pulmonary vascular resistance resulting in pulmonary hypertension (PH) and progressive right heart failure. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodelling. CTEPH mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary artery obliteration [1].To date, the physiopathology of CTEPH remains poorly understood. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation [2]. Besides evidence of dysregulated thrombosis and/or thrombolysis, an elevated prevalence of inflammatory diseases has been observed in CTEPH patients [3]. Accordingly, plasma levels of tumour necrosis factor-a are elevated in CTEPH [4] and elevated pulmonary vascular resistance is correlated with increased expression of the CCL2 chemokine monocyte chemoattractant protein-1 in the plasma and large pulmonary arteries of CTE...

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Section: In Vitro Effects Of Crp On Pulmonary Vascular Cellssupporting

confidence: 90%

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

et al. 2012

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“…Statin also suppresses leptin expression in adipocytes and human coronary artery endothelial cells [18,19]. The effect of statin on leptin expression in VSMCs is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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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“…Vascular damage starts early as Al-Tahami showed that coronary microvascular dysfunction was more prevalent in young obese compared to young lean individuals [14]. Obesity can be associated with elevated CRP concentrations via enhanced leptin secretion and consecutive CRP release from endothelial cells [15]. In addition, Khera et al [16] reported important gender differences regarding body fat pattern resulting in higher CRP levels in obese women compared to men.…”

Section: Discussionmentioning

confidence: 99%

Obesity, Inflammation and Brachial Artery Flow-Mediated Dilatation: Therapeutic Targets in Patients with Microvascular Angina (Cardiac Syndrome X)

Ong

Sivanathan

Borgulya

et al. 2012

Cardiovasc Drugs Ther

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Leptin Stimulated C-Reactive Protein Production by Human Coronary Artery Endothelial Cells

Cited by 54 publications

References 70 publications

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

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

Obesity, Inflammation and Brachial Artery Flow-Mediated Dilatation: Therapeutic Targets in Patients with Microvascular Angina (Cardiac Syndrome X)

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