Abstract
Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, particularly among older adults. Despite the advent of medical technology, restenosis is still an issue after interventional procedures. Tryptophan metabolite 5-methoxytryptophan (5-MTP) has recently been shown to protect against systemic inflammatory responses. This study aimed to investigate the function and mechanisms of 5-MTP in interventional procedure-induced restenosis. We found that after mouse femoral artery denudation with a guide wire, 5-MTP accelerated recovery of endothelium in the denuded area and reduced vascular leakage and intimal thickening. 5-MTP increased endothelial cell proliferation in the denuded arteries and rescued TNF-α-reduced endothelial cell proliferation and migration, likely via maintaining vascular endothelial growth factor receptor 2 activation. In contrast, 5-MTP preserved differentiated phenotype of medial vascular smooth muscle cells (VSMCs) and decreased VSMC proliferation and migration. Furthermore, 5-MTP maintained expression levels of critical transcription factors for VSMC marker gene expressions via attenuated activation of p38 MAPK and NFκB-p65. Our findings uncover a novel protective mechanism of 5-MTP in restenosis. In response to denudation injury, 5-MTP attenuates intimal hyperplasia via concerted but opposing actions on endothelial cells and VSMCs. Taken together, our results suggest that 5-MTP is a valuable therapeutic target for arterial injury-induced restenosis.
Highlights
Cardiovascular disease remains the leading cause of death worldwide and the major global burden of disease, among older adults [1, 2]
Morphometric analysis revealed that 5-MTP significantly decreased intima/media ratio from 1.73±0.35 to 0.73±0.17 (Figure 1G), indicating 5-MTP attenuates intimal hyperplasia after arterial denudation
We demonstrated in an arterial denudation model that tryptophan metabolite 5-MTP protects against intimal hyperplasia via concerted but opposing actions on endothelial cells and vascular smooth muscle cells (VSMCs)
Summary
Cardiovascular disease remains the leading cause of death worldwide and the major global burden of disease, among older adults [1, 2]. In the United States, coronary heart disease (CHD) is the number one cause of deaths attributable to cardiovascular disease [5]. The main underlying cause of CHD is atherosclerosis, a vascular disease progressively occludes the lumen of arteries with atherosclerotic lesions [6]. Interventional procedures can injure blood vessel wall such as removal of the endothelium and medial layer damage, leading to intimal hyperplasia and restenotic lesion formation [7, 8], which remains a critical issue following interventional procedures. Proliferation and migration of medial vascular smooth muscle cells (VSMCs) contribute to neointima formation [9,10,11]. Identifying new complementary therapeutic targets for preventing restenosis is still an unmet medical need
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