Stimulatory Effects of Cardiotrophin 1 on Atherosclerosis

Abstract

A therosclerosis is a pathological injury-to-response process that is initiated by early inflammatory responses of vascular endothelial cells (ECs).1 Endothelial inflammation is characterized by increased production of proatherogenic molecules and inflammatory cytokines in ECs, and monocyte adhesion and infiltration into the neointima lesion, followed by oxidized low-density lipoprotein-induced transformation of macrophages into foam cells.2 Accumulation of cholesterol ester in macrophages is a hallmark of foam cell formation. 2This accumulation depends on the balance between the uptake of oxidized low-density lipoprotein via CD36 and the efflux of free cholesterol controlled by ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1, or scavenger receptor class B type I (SR-BI).3 To protect the cells from the toxicity that would result from excessive free cholesterol accumulation, the free cholesterol is esterified to cholesterol ester by acyl-CoA:cholesterol acyltransferase-1 (ACAT1).3 Cholesterol ester stored in lipid droplets can be removed from cells only after hydrolysis to free cholesterol by neutral cholesterol ester hydrolase. 4 Apart from accumulation of macrophage-derived foam cells, the migration and proliferation of vascular smooth muscle cells (VSMCs) followed by extracellular matrix (ECM) production play crucial roles in the development of atherosclerotic lesions. 1Cardiotrophin 1 (CT-1), a 201-aa member of the interleukin-6 cytokine family, was originally cloned from embryoid bodies as a 21.5-kDa protein capable of inducing hypertrophy in neonatal cardiomyocytes. 5 Human and mouse CT-1 share 80% amino acid sequence identity and exhibit cross-species activity.6 Subsequent studies confirmed that plasma concentrations of CT-1 are elevated in various cardiorenal diseases, such as hypertension, ischemic heart disease, heart failure, and chronic renal disease.7-10 CT-1 exerts cardiovascular remodeling induced by hypertensive and ischemic heart diseases and congestive heart failure, through its receptor complex glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR).11-14 Recently, CT-1 has been shown to be expressed in the intima in the early stages of atherosclerotic lesions in human carotid artery.15 CT-1 stimulates the synthesis of inflammatory cytokines and proatherogenic molecules, such as interleukin-6, Abstract-Cardiotrophin 1 (CT-1), an interleukin-6 family cytokine, was recently shown to be expressed in the intima of early atherosclerotic lesions in the human carotid artery. CT-1 stimulates proatherogenic molecule expression in human vascular endothelial cells and monocyte migration. However, it has not been reported whether CT-1 accelerates atherosclerosis. This study was performed to examine the stimulatory effects of CT-1 on human macrophage foam cell formation and vascular smooth muscle cell migration and proliferation in vitro, and on the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE −/− ) mice in vivo. CT-1 was express...

Cardiotrophin-1: A multifaceted cytokine

“…In contrast, other studies observed that CT-1 increased TNF-a in human peripheral blood mononuclear cells [124] and stimulated monocyte adhesion and migration [125,126] suggesting a contribution to the inflammatory process [125]. In line with these studies, four-week infusion of rCT-1 into ApoE À/À significantly accelerated the development of aortic atherosclerotic lesions [127]. Ló pez-Andres et al reported that chronic exposure of rCT-1 for six weeks was associated with cardiac, vascular and renal fibrosis resulting in further structural and functional damage [35].…”

Cardiotrophin-1: A new predictor of atrial fibrillation relapses after successful cardioversion

“…There are evidence that CT-1 plasma levels can be elevated in patients with hypertension [20], coronary artery disease [21,22], and heart failure [23]. A recent experimental study indicated that CT-1 accelerates the development of atherosclerotic lesions by stimulating the inflammasome, foam cell formation associated with CD36 and acyl-CoA: cholesterol acyltransferase-1 upregulation in macrophages, and migration, proliferation, and collagen-1 production in vascular smooth muscle cells [24]. Our study provided new information on increased CT-1 among persistent AF patients without structural heart disease.…”

Potent Vasoconstrictor Kisspeptin‐10 Induces Atherosclerotic Plaque Progression and Instability: Reversal by its Receptor GPR54 Antagonist

“…Atherosclerosis is a chronic inflammatory response to injury of the arterial wall . Endothelial inflammation stimulates the production of proatherogenic adhesion molecules, such as tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), monocyte chemotactic protein‐1 (MCP‐1), intercellular adhesion molecule‐1 (ICAM‐1), vascular adhesion molecule‐1 (VCAM‐1), and E‐selectin in endothelial cells (ECs).…”

“…Atherosclerosis is a chronic inflammatory response to injury of the arterial wall. 19 Endothelial inflammation stimulates the production of proatherogenic adhesion molecules, such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin in endothelial cells (ECs). These effectors encourage monocyte adhesion and infiltration into the intimal layer, followed by fatty streak formation that is attributed to an accumulation of lipid-laden macrophage foam cells.…”