Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet

Abstract Background Toll-like receptor-2 (TLR2) promotes vascular smooth muscle cell (VSMC) transdifferentiation to chondrocytes and calcification in a p38 MAPK-dependent manner. Vascular 5-methoxytryptophan (5-MTP) is a newly identified factor with anti-inflammatory actions. As 5-MTP targets p38 MA...

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Autores principales:	Guan-Lin Lee, Tsai-Lien Liao, Jing-Yiing Wu, Kenneth K. Wu, Cheng-Chin Kuo
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Chondrogenic differentiation Vascular calcification 5-Methoxytryptophan Toll-like receptor 2 Medicine R
Acceso en línea:	https://doaj.org/article/a55bba9b5f4e4c37833b595349e04928
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spelling	oai:doaj.org-article:a55bba9b5f4e4c37833b595349e049282021-11-14T12:16:01ZRestoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet10.1186/s12929-021-00771-11423-0127https://doaj.org/article/a55bba9b5f4e4c37833b595349e049282021-11-01T00:00:00Zhttps://doi.org/10.1186/s12929-021-00771-1https://doaj.org/toc/1423-0127Abstract Background Toll-like receptor-2 (TLR2) promotes vascular smooth muscle cell (VSMC) transdifferentiation to chondrocytes and calcification in a p38 MAPK-dependent manner. Vascular 5-methoxytryptophan (5-MTP) is a newly identified factor with anti-inflammatory actions. As 5-MTP targets p38 MAPK for its actions, we postulated that 5-MTP protects against vascular chondrogenesis and calcification. Methods High-fat diet-induced advanced atherosclerosis in mice were performed to investigate the effect of 5-MTP on atherosclerotic lesions and calcification. VSMCs were used to determine the role of 5-MTP in VSMC chondrogenic differentiation and calcification. Alizarin red S and Alcian blue staining were used to measure VSMC calcification and chondrogenic differentiation, respectively. Results 5-MTP was detected in aortic tissues of ApoE −/− mice fed control chow. It was reduced in ApoE −/− mice fed high-fat diet (HFD), but was restored in ApoE −/− Tlr2 −/− mice, suggesting that HFD reduces vascular 5-MTP production via TLR2. Intraperitoneal injection of 5-MTP or its analog into ApoE −/− mice fed HFD reduced aortic atherosclerotic lesions and calcification which was accompanied by reduction of chondrogenesis and calcium deposition. Pam3CSK4 (Pam3), ligand of TLR2, induced SMC phenotypic switch to chondrocytes. Pretreatment with 5-MTP preserved SMC contractile proteins and blocked Pam3-induced chondrocyte differentiation and calcification. 5-MTP inhibited HFD-induced p38 MAPK activation in vivo and Pam3-induced p38 MAPK activation in SMCs. 5-MTP suppressed HFD-induced CREB activation in aortic tissues and Pam3-induced CREB and NF-κB activation in SMCs. Conclusions These findings suggest that 5-MTP is a vascular arsenal against atherosclerosis and calcification by inhibiting TLR2–mediated SMC phenotypic switch to chondrocytes and the consequent calcification. 5-MTP exerts these effects by blocking p38 MAPK activation and inhibiting CREB and NF-κB transactivation activity.Guan-Lin LeeTsai-Lien LiaoJing-Yiing WuKenneth K. WuCheng-Chin KuoBMCarticleChondrogenic differentiationVascular calcification5-MethoxytryptophanToll-like receptor 2MedicineRENJournal of Biomedical Science, Vol 28, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Chondrogenic differentiation Vascular calcification 5-Methoxytryptophan Toll-like receptor 2 Medicine R
spellingShingle	Chondrogenic differentiation Vascular calcification 5-Methoxytryptophan Toll-like receptor 2 Medicine R Guan-Lin Lee Tsai-Lien Liao Jing-Yiing Wu Kenneth K. Wu Cheng-Chin Kuo Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet
description	Abstract Background Toll-like receptor-2 (TLR2) promotes vascular smooth muscle cell (VSMC) transdifferentiation to chondrocytes and calcification in a p38 MAPK-dependent manner. Vascular 5-methoxytryptophan (5-MTP) is a newly identified factor with anti-inflammatory actions. As 5-MTP targets p38 MAPK for its actions, we postulated that 5-MTP protects against vascular chondrogenesis and calcification. Methods High-fat diet-induced advanced atherosclerosis in mice were performed to investigate the effect of 5-MTP on atherosclerotic lesions and calcification. VSMCs were used to determine the role of 5-MTP in VSMC chondrogenic differentiation and calcification. Alizarin red S and Alcian blue staining were used to measure VSMC calcification and chondrogenic differentiation, respectively. Results 5-MTP was detected in aortic tissues of ApoE −/− mice fed control chow. It was reduced in ApoE −/− mice fed high-fat diet (HFD), but was restored in ApoE −/− Tlr2 −/− mice, suggesting that HFD reduces vascular 5-MTP production via TLR2. Intraperitoneal injection of 5-MTP or its analog into ApoE −/− mice fed HFD reduced aortic atherosclerotic lesions and calcification which was accompanied by reduction of chondrogenesis and calcium deposition. Pam3CSK4 (Pam3), ligand of TLR2, induced SMC phenotypic switch to chondrocytes. Pretreatment with 5-MTP preserved SMC contractile proteins and blocked Pam3-induced chondrocyte differentiation and calcification. 5-MTP inhibited HFD-induced p38 MAPK activation in vivo and Pam3-induced p38 MAPK activation in SMCs. 5-MTP suppressed HFD-induced CREB activation in aortic tissues and Pam3-induced CREB and NF-κB activation in SMCs. Conclusions These findings suggest that 5-MTP is a vascular arsenal against atherosclerosis and calcification by inhibiting TLR2–mediated SMC phenotypic switch to chondrocytes and the consequent calcification. 5-MTP exerts these effects by blocking p38 MAPK activation and inhibiting CREB and NF-κB transactivation activity.
format	article
author	Guan-Lin Lee Tsai-Lien Liao Jing-Yiing Wu Kenneth K. Wu Cheng-Chin Kuo
author_facet	Guan-Lin Lee Tsai-Lien Liao Jing-Yiing Wu Kenneth K. Wu Cheng-Chin Kuo
author_sort	Guan-Lin Lee
title	Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet
title_short	Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet
title_full	Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet
title_fullStr	Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet
title_full_unstemmed	Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet
title_sort	restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in apoe −/− mice fed high fat diet
publisher	BMC
publishDate	2021
url	https://doaj.org/article/a55bba9b5f4e4c37833b595349e04928
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Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE −/− mice fed high fat diet

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