Unconjugated
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 expressed at high levels in endothelial cells and macrophages in both humans and ApoE(-/-) mice. CT-1 significantly enhanced oxidized low-density lipoprotein-induced foam cell formation associated with increased levels of CD36 and acyl-CoA:cholesterol acyltransferase-1 expression in human monocyte-derived macrophages. CT-1 significantly stimulated the migration, proliferation, and collagen-1 expression in human aortic vascular smooth muscle cells. Four-week infusion of CT-1 into ApoE(-/-) mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration, vascular smooth muscle cell proliferation, and collagen-1 content in the aortic wall. Activation of inflammasome, such as apoptosis-associated speck-like protein containing a caspase recruitment domain, nuclear factor κB, and cyclooxygenase-2, was observed in exudate peritoneal macrophages from ApoE(-/-) mice infused with CT-1. Infusion of anti-CT-1-neutralizing antibody alone into ApoE(-/-) mice significantly suppressed monocyte/macrophage infiltration in atherosclerotic lesions. These results indicate 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.
Cardiotrophin-1 (CTF1) has been reported to act as a trophic factor for a few neurons, such as sensory, cholinergic, dopaminergic, motor and cortical neurons. Studies have indicated that CTF1 delays degenerative disease progression in motor neuron disease. However, little is known about the effects of CTF1 on degenerative disease in the brain. We have shown that expression of CTF1 is strongly down-regulated in the brain of the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease (AD). Transgenic mice with brain tissue-specific CTF1 expression alone or in combination with APPswe/PS1dE9 transgenic mice were produced to study the effects of CTF1 on AD. CTF1 expressing APPswe/PS1dE9 transgenic mice exhibited improvements in learning and memory, less severe abnormalities in locomotor activity, reduced scattered senile plaques and ameliorated disturbances of brain energy metabolism compared to APPswe/PS1dE9 transgenic mice. Furthermore, CTF1 inhibited the activity of glycogen synthase kinase-3β (GSK-3β) in SH-SY5Y cell line and in the brain tissues of APPswe/PS1dE9 transgenic mice. The transgenic expression of CTF1 compensated for the loss of CTF1 expression and brought about a marked improvement on cognitive functioning in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease, suggesting that the inhibition of GSK-3β activity might play an important role.
