Angiotensin II Induces the Expression of C-reactive Protein via MAPK-Dependent Signal Pathway in U937 Macrophages

Abstract

Atherosclerosis is an inflammatory disease in the vessel wall. As an inflammatory molecule, C-reactive protein (CRP) participates in all stages of atherosclerotic process. Although angiotensin II (Ang II) can stimulate the vascular cells to produce CRP, it is unknown whether Ang II induces CRP expression in macrophages. The present study was to observe effect of Ang II on CRP production and the related signal pathway in U937 macrophages so as to provide more evidence for the proinflammatory action of Ang II. The results showed that Ang II significantly increased mRNA and protein expression of CRP in U937 macrophages in time- and concentration-dependent manners. AT₁ receptor blocker losartan blocked Ang II -induced CRP expression in mRNA and protein levels in U937 macrophages. Losartan and complex II inhibitor TIFA decreased Ang II -stimulated reactive oxygen species (ROS) generation, and antioxidant NAC completely abolished Ang II -induced CRP expression in U937 macrophages. The further study indicated that losartan, NAC, MEK1/2 inhibitor PD98059, p38MAPK inhibitor SB203580 obviously inhibited ERK1/2 and p38MAPK phosphorylation, and PD98059, SB203580 and NF-ĸB inhibitor PDTC reduced Ang II -induced mRNA and protein expression of CRP in U937 macrophages. These demonstrate that Ang II is capable of inducing CRP generation in macrophages via AT₁-ROS-ERK1/2/p38MAPK-NF-ĸB signal pathway, which contributes to better understanding of the proinflammatory and proatherosclerotic actions of Ang II.

The balance between human maternal plasma angiotensin II and angiotensin 1-7 levels in early gestation pregnancy is influenced by fetal sex

“…CRP is a non-specific marker of inflammation. Ang II is commonly regarded as a pro-inflammatory peptide which has been shown to stimulate CRP synthesis in vascular endothelial cells, 32 as well as macrophages, 33 and blockade of the Ang II-AT 1 receptor is associated with decreased plasma CRP concentrations. 46 CRP is synthesised by the liver in response to factors released from adipocytes and is known to be associated with obesity.…”

Angiotensin II Induces C-Reactive Protein Expression via AT1-ROS-MAPK-NF-κB Signal Pathway in Hepatocytes

“…In vitro and in vivo experiments in liver have shown that Ang II is able to induce oxidative stress, synthesis of transforming growth factor- β1 and collagen, and to exert proinflammatory actions by stimulating the expression of many proinflammatory cytokines such as intercellular adhesion molecule, IL-6, IL-1β, IL-8, tumor necrosis factor-alpha, cyclooxygenase-2 and iNOS [12,15]. Our previous work suggested that Ang II may induce CRP expression in rat vascular smooth muscle cells (VSMCs), human aortic endothelial cells (HAECs) and macrophages [16,17,18]. …”

Cardioprotective Effect of Losartan Alone or in Combination with Remote Ischemic Preconditioning on the Biochemical Changes Induced by Ischemic/Reperfusion Injury in a Mutual Prospective Study with a Clinical and Experimental Animal Arm

“…Angiotensin II is described as a potent pro-inflammatory mediator causing up regulation of macrophages to induce inflam- 19 Furthermore, angiotensin II has been found to have a dual effect on macrophages through activation of the mitogenactivated protein kinase (MAPK) pathway and up-regulation of early growth response-1 (Egr-1) gene expression which both master the switch for vascular inflammatory responses. 20,21 So, by blocking Ang II signaling, Losartan reduces the inflammatory response as presented in different studies concerned with heart failure treatment outcomes [22][23][24] Losartan induced elevation of NO level in the animal model could reflect the ability of this drug to improve endothelial functions. Losartan by inhibiting angiotensin II receptor may decrease the release of ROS, keeping NO which improves the endothelial function.…”