Roles of Intercellular Adhesion Molecule-1 in Hypertensive Cardiac Remodeling

Abstract

Abstract-Recently, we have shown that in rats with a suprarenal abdominal aortic constriction (AC), pressure overload induces early perivascular fibro-inflammatory changes (transforming growth factor [TGF]-␤ induction and fibroblast proliferation) within the first week after AC and then causes the development of cardiac remodeling (myocyte hypertrophy and reactive myocardial fibrosis) associated with diastolic dysfunction. Intercellular adhesion molecule (ICAM)-1 is implicated in the recruitment of leukocytes, especially macrophages, in various inflammatory situations. Thus, we sought to investigate the causal relation of ICAM-1 to macrophage recruitment and cardiac remodeling in AC rats. In AC rats, immunoreactive ICAM-1 was observed transiently on endothelial cells of the intramyocardial coronary arterioles after day 1, with a peak at day 3, returning to baseline by day 7. Also, ED1 ϩ macrophage accumulation was found in the area adjacent to the arteries expressing ICAM-1. Chronic treatment with an anti-ICAM-1 neutralizing antibody, but not with control IgG, remarkably reduced the accumulations of macrophages and proliferative fibroblasts and inhibited the upregulation of TGF-␤ expression. Furthermore, the neutralizing antibody significantly prevented myocardial fibrosis without affecting arterial pressure and left ventricular and myocyte hypertrophy. In conclusion, ICAM-1 expression was induced by pressure overload in the intramyocardial arterioles, and triggered perivascular macrophage accumulation. In pressure-overloaded hearts, a crucial role in ICAM-1-mediated macrophage accumulation was suggested in the development of myocardial fibrosis, through TGF-␤ induction and fibroblast activation.

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

“…9,10 AC-induced inflammatory changes result in myocardial fibrosis in the early phase and diastolic dysfunction in the later phase. 9,11,12,19 In this study, AC induced cardiac remodeling and diastolic dysfunction associated with inflammatory changes and superoxide generation in control female rats. A growing body of evidence implicates vascular inflammation in cardiovascular diseases in postmenopausal hypertensive women.…”

“…13 A causal relationship between inflammation and reactive myocardial fibrosis and diastolic dysfunction has been established in AC rats: a neutralizing antibody against MCP-1 or intercellular adhesion molecule-1 not only abolished macrophage infiltration but also inhibited fibroblast proliferation, TGF-b upregulation and myocardial fibrosis in AC rats. 9,12 Anti-MCP-1 neutralizing antibody prevented the progression of diastolic dysfunction in AC rats. 9 The augmentation of cardiac inflammation induced by estrogen deficiency is implicated in the aggravation of myocardial fibrosis and diastolic dysfunction in OVX+AC rats.…”

“…9,10 The inflammatory changes trigger reactive myocardial fibrosis, which is the major cause of diastolic dysfunction in this model. 9,11,12 Estrogen deficiency augments MCP-1 expression and inflammation after vascular injury in rats undergoing bilateral ovariectomy (OVX). 13 Thus, cardiac inflammatory changes may be enhanced by estrogen deficiency in individuals with hypertension, which may negatively affect diastolic dysfunction in postmenopausal females with hypertension.…”

Exaggerated Blood Pressure Variability Superimposed on Hypertension Aggravates Cardiac Remodeling in Rats via Angiotensin II System-Mediated Chronic Inflammation

“…[17][18][19][20] In addition, we have shown that a subdepressor dose of candesartan not only prevents MCP-1 induction and macrophage infiltration but also ameliorates reactive myocardial fibrosis in pressure-overloaded hearts. 21 These findings suggest that the cardiac angiotensin II (angII) system triggers the fibroinflammatory process, independent of its pressor effect.…”

Inflammatory markers are associated with left ventricular hypertrophy and diastolic dysfunction in a population-based sample of elderly men and women

“…Also, macrophages accumulated in the area adjacent to the arteries showing ICAM-1 expression. 6 The involvement of mast cells in the development of fibrosis in rats with postmyocarditis-dilated cardiomyopathy has been investigated and a significant correlation between myocardial fibrosis and cardiac mast cell density was obtained. The findings confirm the active participation of mast cells in the progression of myocardial fibrosis in rats with postmyocarditis-dilated cardiomyopathy.…”