Role of Transforming Growth Factor-β1 in Cardiovascular Inflammatory Changes Induced by Chronic Inhibition of Nitric Oxide Synthesis

Abstract

Abstract-We previously reported that chronic inhibition of nitric oxide (NO) synthesis with N -nitro-L-arginine methyl ester (L-NAME) induces inflammatory changes (monocyte infiltration, myofibroblast formation, and monocyte chemoattractant protein-1 [MCP-1] and transforming growth factor-␤1 [TGF-␤1] expression) in the rat heart and vessel. There is debate regarding whether TGF-␤1 exhibits proinflammatory or anti-inflammatory activities. We used the rat model to investigate the role of TGF-␤ in the pathogenesis of such inflammatory changes. We show here that infiltrating monocytes and myofibroblasts in the inflammatory lesions produced TGF-␤1 on the third day of L-NAME administration. Cotreatment with a monoclonal antibody against TGF-␤1, but not with control IgG, prevented the L-NAME-induced cardiac inflammation. The antibody also significantly inhibited the gene expression of MCP-1, P-selectin, and intercellular adhesion molecule-1. In summary, the antibody against TGF-␤1 prevented inflammatory changes in rat heart and vessel induced by chronic inhibition of NO synthesis, suggesting that increased production of TGF-␤1 is involved in the inflammatory changes in this model. Key Words: endothelium-derived factor Ⅲ growth substances Ⅲ inflammation Ⅲ adhesion molecule Ⅲ angiotensin II Ⅲ fibrosis C ardiovascular disorders such as hypertension, hypercholesterolemia, atherosclerosis, and aging are associated with endothelial dysfunction that leads to the reduced bioactivity of nitric oxide (NO). 1-7 We 8 -12 and others 13 have recently shown that chronic inhibition of NO synthesis with N -nitro-L-arginine methyl ester (L-NAME) induces marked monocyte infiltration into the coronary vessels associated with induction of monocyte chemoattractant protein-1 (MCP-1) during the first week of the treatment and causes vascular remodeling (medial thickening and fibrosis) and myocardial remodeling (fibrosis and hypertrophy) after 4 to 8 weeks of the treatment in animals.We have recently reported that early induction of transforming growth factor-␤1 (TGF-␤1) contributes to cardiac fibrosis in this model. 10 However, the role of TGF-␤1 in the pathogenesis of early inflammatory changes in this model has not been examined. There is considerable debate regarding whether TGF-␤1 exhibits proinflammatory or antiinflammatory activities (for review, see References 14 and 15). For example, it has been demonstrated that in vivo gene transfer of TGF-␤1 causes tissue inflammatory changes and subsequent fibrosis in the lung 16 and blood vessels, 17 whereas the major phenotype of the TGF-␤1 knockout mice is an early-onset inflammation in most tissues of the body. 18,19 TGF-␤1 is usually secreted from many cell types as a biologically inactive or latent form. 20 The activation mechanisms of latent TGF-␤1 complex in vivo have not been fully elucidated. Thus, demonstration of mere expression of total TGF-␤1 may not provide sufficient evidence of its function. To address direct in vivo evidence for the functional importance of TGF-␤1, a neutralizing...

Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats

“…9 -11 It has been shown that an anti-pan-TGF-␤ monoclonal NAb effectively prevents the expression of extracellular matrix proteins and subsequent myocardial fibrosis in rats with long-term blockade of nitric oxide synthesis. 12 Therefore, using the NAb, we investigated the roles of TGF-␤ in myocardial remodeling in PO rats with a suprarenal abdominal aortic constriction (AC). Also, we examined whether prevention of myocardial remodeling by blocking TGF-␤ function would improve cardiac dysfunction in PO rats.…”

Transforming Growth Factor-β 1 Modulates Oxidatively Modified LDL–Induced Expression of Adhesion Molecules

“…10 -12 Growth factors, such as transforming growth factor-␤ 1 (TGF-␤ 1 ), have been shown to modulate the expression of adhesion molecules. [13][14][15][16] TGF-␤ 1 , a member of the family of growth factors, is a multifunctional polypeptide. 17 It manifests its biological effects by binding to three distinct TGF-␤ 1 receptors on cell surface (type 1, 2 and 3 [including endoglin]).…”

“…18 -20 There is evolving evidence that TGF-␤ 1 regulates proliferation and differentiation of cells, remodeling of blood vessels and myocardium after injury, angiogenesis, inflammation, release of cytokines, and lipid metabolism. 10,[15][16][17][18][21][22][23] In keeping with the potential role that TGF-␤ 1 may play in adhesion molecule expression and possibly atherogenesis, Koglin et al 24 showed more extensive atherosclerosis in TGF-␤ 1 -knockout mice. Grainger et al, 25 and later Tashiro et al, 26 showed reduced plasma TGF-␤ 1 levels in patients with atherosclerosis.…”

Screening of KMU-4, 6, 7 on inflammatory responses in IFN-γ and LPS-induced mouse peritoneal macrophages

“…NO has been recognized to be an important mediator of cellular communication in several preparations such as macrophages, neutrophils, smooth muscle, autonomic nervous system, and central nervous system (Blackman et al, 2000;Koyanagi et al, 2000;Sharma et al, 2000). In this study, exposure of macrophages to IFN-γ and LPS for 48 h was associated with an accumulation of nitrite in the medium, suggesting an enhanced NO production.…”