An Angiotensin-Converting Enzyme Inhibitor Suppresses the Expression of Vascular Cell Adhesion Molecule-1 and Production of Cytokines Induced in Activated Endothelial Cells

Abstract

Summary Quinaprilat, an angiotensin-converting enzyme (ACE) inhibitor, is commonly used for the therapy of hypertension, but the influence of ACE inhibitor for the atherogenesis has not been clear. Then we investigated the suppressive effect of ACE inhibitor on the expression of adhesion molecules and the production of cytokines which play an important role in the early development of atherosclerosis in endothelial cells (ECs). Quinaprilat treatment significantly reduced the activation of nuclear factor-KB (NF-KB), the surface expression of vascular cell adhesion molecule-1 (VCAM-1), the production of cytokines such as monocyte chemoattractant protein-1 and interleukin-6, and the number of mononuclear leukocytes adhering to ECs induced by tumor necrosis factor-a (TNF-a) and oxidized low-density lipoprotein (oxLDL). This suppressive effect was diminished by both a kinin B2 receptor antagonist and a nitric oxide synthase (NOS) inhibitor. These results indicated that quinaprilat reduced the activation of NF-KB under the stress of chemoattractants such as TNF-a and oxLDL through the increase of endothelial nitric oxide (NO) produced by activated endothelial nitric oxide synthase (eNOS) via a secondary accumulation of bradykinin in ECs. These results suggest an anti-atherogenic effect of ACE inhibitor.

The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

“…The anti-inflammatory and antiatherogenic effects of ACE inhibitors, alone or in combination with other drugs, have been investigated in previous preclinical (Chen et al, 2003;Da Cunha et al, 2005;Hayek et al, 1999;Hayek et al, 2002;Hernández-Presa et al, 1998;Husain, Suarez, Isidro, & Ferder, 2010;Knowles et al, 2000;Ochiai et al, 2002;Schlimmer, Kratz, Böhm, & Baumhäkel, 2011;Shimozawa et al, 2004;Yang et al, 2013) and clinical studies (Ceconi et al, 2009;Han et al, 2012;Lonn et al, 2001;McMurray et al, 2006;Mitrovic et al, 2005;Zanchetti et al, 2004). Shimozawa et al (2004) showed that treatment of human aortic endothelial cells Furthermore, treatment with enalapril interrupted the cycle of atheroma formation and kidney damage in mice that were atherosclerotic and hypertensive due to lack of ApoE and eNOS.…”

“…The anti‐inflammatory and antiatherogenic effects of ACE inhibitors, alone or in combination with other drugs, have been investigated in previous preclinical (Chen et al, ; Da Cunha et al, ; Hayek et al, ; Hayek et al, ; Hernández‐Presa et al, ; Husain, Suarez, Isidro, & Ferder, ; Knowles et al, ; Li, Zhang, et al, ; Ochiai et al, ; Schlimmer, Kratz, Böhm, & Baumhäkel, ; Shimozawa et al, ; Yang et al, ) and clinical studies (Ceconi et al, ; Han et al, ; Lonn et al, ; McMurray et al, ; Mitrovic et al, ; Zanchetti et al, ). Shimozawa et al () showed that treatment of human aortic endothelial cells (HAECs) with alacepril inhibited the expression of intercellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) and reduced the adhesion of monocyte following treatment with 7‐ketocholesterol or tumor necrosis factor (TNF)‐α‐stimulated HAECs.…”

“…Quinaprilat treatment was shown to reduce the activation of NF-κB, the surface expression of VCAM-1, the production of monocyte chemotactic protein-1 (MCP-1) and interleukin (IL)-6, and the number of mononuclear leukocytes adhering to endothelial cells induced by TNF-α and oxidized low-density lipoprotein (Ox-LDL). These antiatherogenic effects of quinaprilat were suggested to be due to increased production of endothelial nitric oxide resulting from activated endothelial nitric oxide synthase (eNOS;Ochiai et al, 2002). In apolipoprotein (Apo) E-deficient mice, enalapril treatment (25 mg/kg/day) prevented the Ang II-induced overexpression of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) and chemokines MCP-1 in the aorta, while upregulated the expression of potential anti-inflammatory transcription factors peroxisome proliferator-activated receptors (PPARs)-α and -ƴ, suggesting the role of Ang II-independent mechanisms in the antiinflammatory and antiatherogenic effects of ACE inhibitors(Da Cunha et al, 2005).…”