Régulation de protéine C-réactive vasculaire dans le diabète de type 2
Atherosclerotic cardiovascular disease is the leading cause of death in western countries and the major complication of metabolic syndrome. It is now widely accepted that atherosclerosis is a chronic inflammatory disease and that inflammation plays a major pathogenic role in the initiation and progression of atherosclerotic disease. It has been demonstrated that increased serum levels of C-reactive protein (CRP), a protein of the acute phase and a major constituent of the innate immune response, is associated with increased cardiovascular risk and that, in both healthy subjects and diabetic patients, high CRP enhances the risk of cardiovascular morbidity and mortality. Several evidences suggest that CRP may not only be a cardiovascular risk marker but may also represent a direct pro-atherogenic factor. Endothelial dysfunction is a characteristic feature of early-state atherosclerosis and a role of CRP in the pathogenesis of endothelial dysfunction has been proposed. In addition to its systemic origin, CRP is produced in atherosclerotic lesions and by various vascular cells, including endothelial cells. To elucidate the role of CRP in endothelial dysfunction associated with the metabolic syndrome, we studied the regulation of endothelial CRP expression by free fatty acids (FFA) and the role of endothelial CRP as mediator of the inhibitory effect of FFA on nitric oxide (NO) production. Our results demonstrated that: 1) Palmitic acid (PA) induced CRP gene expression in cultured human arterial endothelial cells (HAECs) and increased CRP protein expression in a dose-dependent manner; 2) Pretreatment of HAECs with antioxidants and inhibitors of i) protein kinase C (PKC), ii) nuclear factor-kappa B, iii) Janus kinase and signal transducer and activator of transcription and iv) mitogen-activated protein kinases prevented the stimulatory effect of PA on CRP protein and gene expression; 3) Treatment of HAECs by PA led to an increased production of reactive oxygen species, an effect prevented by PKC inhibitors and by AICAR (5-amino-4-imidazole carboxamide 1-β-D-ribofuranoside), an AMP-  activated protein kinase activator; 4) Decreased production of NO was finally observed in PA-treated HAECs, an effect prevented by preincubating endothelial cells with an anti-CRP.  Overall, these data indicate a stimulatory effect of PA on endothelial CRP expression through the activation of oxidative stress-sensitive kinases and transcription factors. They further suggest a role of CRP in FFA-induced endothelial dysfunction.
PA inflammation CRP Metabolic syndrome insulin resistance oxidative stress PA atherosclerosis cardiovascular diseases endothelial cells inflammation C-reactive protein type 2 diabetes