PubMed · 13639031
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V RAPANT, V MACAK, J DOUBRAVSKY. 1959-03-13. [Double aortic arch].. https://pubmed.ncbi.nlm.nih.gov/13639031/
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OBJECTIVE: To study the stiffness of large arteries in relation to the extent of skin and lung fibrosis, aortic distensibility was examined in patients with diffuse and limited systemic sclerosis (SSc). METHODS: Consecutive patients (55 with diffuse and 51 with limited SSc) without signs and symptoms of heart failure or a previous history of arterial hypertension underwent echocardiography and lung function tests. Aortic stiffness was determined non-invasively by aortic distensibility and aortic strain measurements in all patients and in 50 healthy subjects, matched for age and gender. RESULTS: Aortic distensibility in patients with either diffuse (2.03 +/- 0.26 x 10(-6) cm(2) dyn(-1)) or limited SSc (2.12 +/- 0.33) was similarly decreased compared with controls (2.49 +/- 0.36, P<0.001). Moreover, aortic strain was significantly reduced in both patient groups compared with controls, confirming that aortic stiffness is increased in SSc independently of the extent of skin involvement. Left ventricular performance was similar between patients and controls, while left ventricular mass and tricuspid systolic gradient were significantly increased in both SSc groups, the latter being associated with aortic stiffness in multivariate analysis. No association with serum levels of C-reactive protein or lung function abnormalities indicative of pulmonary fibrosis were found. CONCLUSIONS: Stiffness of the aorta is increased in patients with established SSc regardless of the extent of the inflammatory fibrotic process in the skin and lungs, suggesting that additional pathogenetic mechanisms contribute to the compromise of large arteries.
BACKGROUND: Resistin, a novel adipokine, is elevated in patients with type 2 diabetes and may play a role in the vascular complications of this disorder. One recent study has shown that resistin has a proinflammatory effect on endothelial cells. However, there is no information on whether resistin could also affect vascular smooth muscle cells (SMCs). Thus, the purpose of this study was to assess whether resistin could induce SMC proliferation and to study the mechanisms whereby resistin signals in SMCs. METHODS AND RESULTS: Human aortic smooth muscle cells (HASMCs) were stimulated with increasing concentrations of resistin for 48 hours. Cell proliferation was induced by resistin in a dose-dependent manner as assessed by direct cell counting. To gain more insights into the mechanism of action of resistin, we investigated the extracellular signal-regulated kinase (ERK) and/or phosphatidylinositol 3-kinase (PI3K) signaling pathways. Transient phosphorylation of the p42/44 mitogen-activated protein kinase (ERK 1/2) occurred after addition of resistin to HASMCs. U0126, a specific inhibitor of ERK phosphorylation, significantly inhibited ERK 1/2 phosphorylation and reduced resistin-simulated proliferation of HASMCs. LY294002, a specific PI3K inhibitor, also significantly inhibited HASMC proliferation after resistin stimulation. CONCLUSIONS: Our results demonstrate that resistin induces HASMC proliferation through both ERK 1/2 and Akt signaling pathways. The proliferative action exerted by resistin on HASMCs may account in part for the increased incidence of restenosis in diabetes patients.
OBJECTIVE: C-reactive protein (CRP) is the prototype acute phase protein and a cardiovascular risk factor. Interleukin-1beta (IL-1beta) and IL-6 stimulate CRP synthesis in hepatocytes. We searched for additional pathways regulating CRP expression. METHODS AND RESULTS: Primary human hepatocytes (PHHs) were treated with IL-1beta, IL-6, and protein kinase C (PKC) activator phorbol 12,13-dibutyrate (PDBu). CRP was analyzed by quantitative RT-PCR and ELISA. PDBu significantly induced CRP transcription by 21.0+/-9.24-fold and protein release by 2.9+/-0.5-fold. Transcriptional regulation was studied in detail in hepatoma G2 (HepG2) cells stably transfected with the 1-kb CRP promoter (HepG2-ABEK14 cells). In these cells, PDBu significantly induced CRP transcription by 5.39+/-0.66-fold. Competitive inhibition with bisindolylmaleimide derivative LY333531 abolished PDBu-mediated promoter activation. Competitive inhibition with IkappaB kinase inhibitor I229 also inhibited PDBu effects. Importantly, IL-8 significantly induced CRP release in PHHs by 58.675+/-19.1-fold, which was blockable by LY333531. CONCLUSIONS: This study describes a novel PKC-dependent transcriptional regulation of CRP gene expression, which, in analogy to the classical IL-1beta and IL-6 pathways, is operational in hepatocytes only. It also identifies IL-8 as a potential physiological PKC activator. HepG2-ABEK14 cells may be useful for high throughput screening to identify inhibitors of CRP synthesis for the prevention of cardiovascular disease.