imidapril and Inflammation

Angiotensin-converting enzyme inhibitors (ACEIs) are used to control hypertension and are superior to other antihypertensive agents in protecting the progressive deterioration of autoimmune-related nephritis. An imbalance of T helper 1 (Th1)/Th2 is thought to contribute to the pathogenesis of autoimmune diseases and their related glomerulonephritis. I-309 is a Th2-related chemokine involved in the recruitment of Th2 cells toward Th2-related inflammation. Tumor necrosis factor α (TNF-α) and Th1-related chemokines, interferon-inducible protein 10 (IP-10)/CXCL10 are also involved in autoimmune glomerulonephritis. However, the modulatory effects and the mechanisms of ACEIs on TNF-α and Th1- and Th2-related chemokines in monocytes remain poorly defined.. We investigated the effects of imidapril and perindopril, 2 ACEIs, on the expression of IP-10, I-309, and TNF-α in human monocytes and also the associated intracellular mechanism.. Imidapril and perindopril significantly downregulated lipopolysaccharide (LPS)-induced TNF-α, I-309, and IP-10 in THP-1 cells and human primary monocytes. All 3 mitogen-activated protein kinase inhibitors suppressed LPS-induced TNF-α and I-309 expression in human primary monocytes. Only extracellular signal-regulated kinases and c-Jun N-terminal kinases (JNK) mitogen-activated protein kinase inhibitors suppressed LPS-induced IP-10 expression. Lipopolysaccharide-induced mitogen-activated protein kinase kinase 4 (MKK4), p-JNK, and c-Jun expression in human primary monocytes was suppressed by imidapril.. These data demonstrate that ACEI is effective in downregulating LPS-induced TNF-α, I-309, and IP-10, which play important roles in the pathogenesis of inflammation. Its suppressive effect on TNF-α, I-309, and IP-10 may, at least in part, involve the down-regulation of LPS-induced MKK4-JNK-c-Jun expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Chemokine CCL1; Chemokine CXCL10; Chemokines; Cytokines; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Imidazolidines; Inflammation; Lipopolysaccharides; MAP Kinase Kinase 4; MAP Kinase Signaling System; Monocytes; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha

Recent evidence indicates that renin-angiotensin system (RAS) plays an important role in the pathogenesis of atherosclerosis. It was reported that inhibition of RAS with angiotensin II type 1 receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs) is effective in prevention of atherosclerosis. Here, we investigated the effects of an ARB or/and an ACEI on atherosclerosis development and periadventitial inflammation in apolipoprotein E (ApoE)-deficient mice. RT-PCR revealed that major RAS components were expressed in periaortic tissue. Ang II infusion significantly increased accumulation of bone marrow derived cells into both neointima (p<0.05) and periaortic tissue (p<0.01). Male ApoE- deficient mice were treated with either vehicle, TA606A (10mg/kg/day, ARB), imidapril (3mg/kg/day, ACEI) or TA606A plus imidapril (TA606A 10mg/kg/day+imidapril 3mg/kg/day, ARB+ACEI) for 24 weeks starting at 12 weeks of age. ARB, ACEI, and ARB+ACEI significantly reduced atherosclerotic lesion formation in aorta compared with vehicle (p<0.05), with reduced expression of monocyte chemoattractant protein-1 in periaortic tissues (p<0.01). Neither blood pressure nor heart rate was changed by the treatments at these lower doses. Imidapril significantly reduced lipid deposition in atheroma and plasminogen activator inhibitor-1 expression in periadventitial tissue (p<0.05, respectively). Imidapril and combination therapy significantly attenuated macrophage infiltration into the atherosclerotic plaque (p<0.05, respectively). All treatments reduced macrophage accumulation in the periadventitial tissue 12 weeks after treatment (p<0.05, respectively). These results suggest that inhibition of renin-angiotensin system attenuates periadventitial inflammation and reduces atherosclerotic lesion formation.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Chemokine CCL2; Connective Tissue; Gene Expression Regulation; Imidazoles; Imidazolidines; Inflammation; Male; Mice; Mice, Knockout; Pyridines; Renin-Angiotensin System; Tetrazoles

To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arterial Occlusive Diseases; Bradykinin Receptor Antagonists; Cell Division; Chemokine CCL2; Constriction; Enzyme Inhibitors; Imidazoles; Imidazolidines; Immunohistochemistry; Inflammation; Male; Mice; Mice, Knockout; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B2; Receptors, Angiotensin; Reverse Transcriptase Polymerase Chain Reaction; Tumor Necrosis Factor-alpha