Fibrinopeptide A Induces Expression of C-Reactive Protein via the ROS-ERK1/2/ P38-NF-κB Signal Pathway in Vascular Smooth Muscle Cells

Abstract

Background/Aims: Atherosclerosis is a chronic inflammatory disease in the artery walls. Fibrinopeptide A (FPA) is a biomarker of the activation of coagulation system, and a high concentration of FPA in blood occurs in patients with ischemic heart disease etc. However, there exist few studies on the pathological effects of FPA in cardiovascular system. Therefore, the present study examined the effect of FPA on CRP expression in VSMCs and the molecular mechanisms. Methods: mRNA and protein expression was identified by quantitative real-time PCR and Western blot, respectively. Reactive oxygen species (ROS) and the immunofluorescence staining were observed by a fluorescence microscope. Plasma FPA and CRP level was determined by ELISA. Results: FPA induced the expressions of CRP, IL-1β and IL-6 in VSMCs, and anti-IL-1β and anti-IL-6 neutralizing antibodies partially reduced FPA-induced CRP expression in VSMCs. The subchronic administration of FPA to rats increased FPA level in plasma and CRP expression in the aortic artery walls. The further studies showed that FPA promoted superoxide anion generation in VSMCs. Antioxidant NAC antagonized FPA-stimulated superoxide anion generation and inhibited FPA-induced CRP expression in VSMCs. FPA activated ERK1/2 and p38 phosphorylation, and PD98059 and SB203580 reduced FPA-induced CRP expression. Moreover, NAC inhibited the activation of ERK1/2 and p38. In addition, FPA enhanced NF-κB level in the nuclei of VSMCs, and PDTC reduced FPA-induced expression of CRP. Conclusions: FPA induces CRP expression in VSMCs via ROS-ERK1/2/p38-NF-κB signal pathway. This finding for the first time provides an experimental evidence for pro-inflammatory effect of FPA.

Impact of C-reactive protein on osteo-/chondrogenic transdifferentiation and calcification of vascular smooth muscle cells

“…VSMCs express CRP and, thus, CRP is also produced locally in the vasculature [19,66–68]. The present findings show that CRP expression is increased in VSMCs during calcifying conditions in vitro as well as in the vascular tissue of the klotho-hypomorphic mouse model of aging and CKD-related vascular calcification.…”

“…However, in our in vitro model, aldosterone did not significantly influence CRP expression or CRP-induced osteo-/chondrogenic transdifferentiation of VSMCs. In addition, cellular oxidative stress [19,66–68] and p38 MAPK pathway activation [66,67] may further augment CRP expression in VSMCs and, thus, increase local CRP concentrations leading to an amplification of the pro-calcific effects. Thus, in complex pathological conditions such as CKD, elevated systemic CRP levels as well as locally produced CRP may directly contribute to the progression of vascular calcification.…”

<p>Inhibitory Effect of Curcumin on Artery Restenosis Following Carotid Endarterectomy and Its Associated Mechanism in vitro and in vivo</p>

“…Pintus et al reported that activation of the PKC/Raf/MEK/ERK pathway could regulate blood lipid levels and increase the risk of atherosclerosis by increasing the expression of native LDL and E2F-1. 32 The activation of ERK1/2 plays an important role in this pathway 33,34 and inhibition of ERK1/2 activation can inhibit the phosphorylation of MAPK, thereby regulating cell proliferation and migration. In addition, the activation of ERK1/2 can increase the expression of the downstream nuclear transcription factor NF-κB and the cell cycle proteins, such as Cyclin D1, which leads to a change in cell proliferation.…”

Patient Stratification in Sepsis: Using Metabolomics to Detect Clinical Phenotypes, Sub-Phenotypes and Therapeutic Response

“…Patients who did not survive showed a greater disruption in carnitine metabolism with the acetylcarnitine to carnitine ratio (AC:C) being significantly higher in non-survivors prior to treatment, which then fluctuated more with time [ 143 ]. In another study of L-carnitine supplementation, within those patients who received L-carnitine, non-survivors had elevated levels of fibrinopeptide A, a marker of coagulation [ 145 ] which also induces C-reactive protein expression in vascular smooth muscles [ 146 ]; glucosamine, an anti-inflammatory agent formed during wound healing and tissue injury and repair [ 147 ]; histamine, which enhances vascular permeability [ 148 ]; allysine, a derivative of lysine involved in the synthesis and cross linking of collagen and elastin [ 149 ]; and N-(3-acetamidopropyl)pyrrolidin-2-one, a product of spermidine catabolism [ 150 ] in comparison to survivors, whilst phenylalanyl-tyrosine, a dipeptide of tyrosine and phenylalanine which is involved in the production of catecholamines [ 35 ], and N-acetyl-L-phenylalanine were reduced [ 90 ].…”