Molecular Mechanisms Mediating Inflammation in Vascular Disease

Abstract

Abstract-There are several clinical challenges for the treatment of intractable cardiovascular diseases, including restenosis, atherosclerotic complications resulting from plaque rupture, severe tissue ischemia, and heart failure. Emerging evidence suggests that an inflammatory process is involved in the pathogenesis of such intractable diseases.In particular, inflammatory responses to arterial injury, which cause continuous recruitment and activation of monocytes mainly through activation of the monocyte chemoattractant protein- The effects of MCP-1 are mediated mainly through CC chemokine receptor 2 (CCR2). 3,4 MCP-1 causes chronic vascular inflammation and induces thrombosis, proliferation and migration of vascular smooth muscle cells, angiogenesis, and oxidative stress (Figure 1). Previous studies indicate that (1) MCP-1 production from endothelial cells, smooth muscle cells, and lesional leukocytes increases in the presence of endothelial dysfunction and atherosclerotic risk factors ( Figure 1); (2) MCP-1 expression is increased in atherosclerotic lesions 5,6 and injured arteries 7,8 ; and (3) eliminating MCP-1 function decreases neointimal hyperplasia after injury and atheroma formation in mice. 9 -12 We demonstrated that MCP-1 has an important role in coronary arteriosclerosis in a rat model of NO synthesis inhibition. [13][14][15][16][17] Emerging evidence suggests that MCP-1-mediated inflammatory disorders are involved in restenosis and atherosclerosis, as well as in other treatment-intractable cardiovascular diseases, such as posttransplantation arteriosclerosis, vascular remodeling owing to hypertension, myocarditis/cardiomyopathy, and cardiac dysfunction and remodeling after myocardial infarction. 18 -23 Therefore, therapeutic strategies targeting MCP-1 might become useful and practical treatments for cardiovascular diseases that are intractable with conventional therapies. In this regard, we devised a new strategy for anti-MCP-1 gene therapy by transfecting mutant MCP-1 gene. 17,24 This strategy might be useful for clarifying the role of MCP-1 under pathophysiologic conditions in vivo. In this review, we describe the role of MCP-1 in cardiovascular

Anti—Monocyte Chemoattractant Protein-1 Gene Therapy Protects against Focal Brain Ischemia in Hypertensive Rats

“…MCP-1 is involved in several inflammatory diseases, including rheumatoid arthritis (Koch et al, 1992), nephritis (Panzer and Stahl, 1999), infections (Dawson et al, 2000;Sato et al, 1999), and atherosclerosis (Egashira, 2003;Yla-Herttuala et al, 1991). These data indicate that MCP-1 is one of the major proinflammatory cytokines.…”

“…We have recently reported that an N-terminal deletion mutant of human MCP-1 gene (7ND), which lacks the N-terminal amino acids 2 to 8, acts as a dominant nega-tive inhibitor for MCP-1 and blocks the MCP-1/CCR2 signal pathway in vivo (Egashira et al, 2000;Egashira, 2003). This mutant MCP-1 and normal MCP-1 form a heterodimer, which binds to the MCP-1 receptor (CCR-2) and completely inhibits MCP-1-mediated monocyte chemotaxis in vitro (Rollins, 1996).…”

Endothelial dysfunction is associated with increased levels of biomarkers in essential hypertension

“…28,29 Furthermore, MCP-1 is also responsible for monocyte recruitment and trafficking, and has been found in both human and animal atherosclerotic lesions. 30 They have all been related to the risk of future cardiovascular events in healthy women 31 and especially in patients with coronary artery disease. 21,22 We have previously reported increased levels of these biomarkers in salt-sensitive hypertensive patients, 25 irrespective of the level of salt intake, a group also characterized by a more impaired endothelial function.…”

Oxidized Omega-3 Fatty Acids Inhibit NF-κB Activation Via a PPARα-Dependent Pathway

“…MCP-1 and IL-8 in turn promote leukocyte chemotaxis, adhesion, and transendothelial migration, 13,14 and neutralization of MCP-1 has been shown to attenuate in vivo injury arising from inflammatory mechanisms. [15][16][17] The aim of this study was to determine the effects of oxidized versus native omega-3 fatty acids on the endothelial expression of chemokines MCP-1 and IL-8, and, if effective in inhibiting chemokine expression, to determine the mechanism for the inhibition of chemokine expression.…”