Shh–Gli2–Runx2 inhibits vascular calcification
ABSTRACT Background In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unc...
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| Veröffentlicht in: | Nephrology, dialysis, transplantation dialysis, transplantation, 2024-01, Vol.39 (2), p.305-316 |
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| creator | Huang, Aoran Xu, Tianhua Lu, Xiaomei Ma, Ling Ma, Haiying Yu, Yanqiu Yao, Li |
| description | ABSTRACT
Background
In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC.
Methods
Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC.
Results
Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B.
Conclusions
Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.
Graphical Abstract
Graphical Abstract |
| doi_str_mv | 10.1093/ndt/gfad165 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2838251648</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/ndt/gfad165</oup_id><sourcerecordid>2838251648</sourcerecordid><originalsourceid>FETCH-LOGICAL-c278t-8f00c389aa9d8c7c2d6d2f55782e0428c00953271c8f67007d0fcde92d8408f93</originalsourceid><addsrcrecordid>eNp9kMtKAzEUhoMotl5W7qUrEWTsSTKZnFlK0SoUBC_rkOZiI9OZOpkR3fkOvqFPYqTVpat_cT4-Dh8hRxTOKZR8XNtu_OS1pYXYIkOaF5AxjmKbDNOVZiCgHJC9GJ8BoGRS7pIBl7mgSHFI2P1i8fXxOa0CS3PX129sFOpFmIcujl51NH2l25HRlQk-GN2Fpj4gO15X0R1udp88Xl0-TK6z2e30ZnIxywyT2GXoAQzHUuvSopGG2cIyL4RE5iBnaNI3gjNJDfpCAkgL3lhXMos5oC_5Pjlde1dt89K72KlliMZVla5d00fFkCMTtMgxoWdr1LRNjK3zatWGpW7fFQX1E0mlSGoTKdHHG3E_Xzr7x_5WScDJGmj61b-mb__WcM4</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2838251648</pqid></control><display><type>article</type><title>Shh–Gli2–Runx2 inhibits vascular calcification</title><source>MEDLINE</source><source>Free E-Journal (出版社公開部分のみ）</source><source>Alma/SFX Local Collection</source><source>Oxford Journals</source><creator>Huang, Aoran ; Xu, Tianhua ; Lu, Xiaomei ; Ma, Ling ; Ma, Haiying ; Yu, Yanqiu ; Yao, Li</creator><creatorcontrib>Huang, Aoran ; Xu, Tianhua ; Lu, Xiaomei ; Ma, Ling ; Ma, Haiying ; Yu, Yanqiu ; Yao, Li</creatorcontrib><description>ABSTRACT
Background
In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC.
Methods
Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC.
Results
Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B.
Conclusions
Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.
Graphical Abstract
Graphical Abstract</description><identifier>ISSN: 0931-0509</identifier><identifier>ISSN: 1460-2385</identifier><identifier>EISSN: 1460-2385</identifier><identifier>DOI: 10.1093/ndt/gfad165</identifier><identifier>PMID: 37451818</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adenine ; Animals ; Core Binding Factor Alpha 1 Subunit - genetics ; Core Binding Factor Alpha 1 Subunit - metabolism ; Hedgehog Proteins - genetics ; Hedgehog Proteins - metabolism ; Hedgehog Proteins - pharmacology ; Humans ; Mice ; Myocytes, Smooth Muscle - metabolism ; Phosphorus - metabolism ; Renal Insufficiency, Chronic - pathology ; Vascular Calcification - etiology ; Vascular Calcification - metabolism ; Vascular Calcification - prevention & control</subject><ispartof>Nephrology, dialysis, transplantation, 2024-01, Vol.39 (2), p.305-316</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. 2023</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c278t-8f00c389aa9d8c7c2d6d2f55782e0428c00953271c8f67007d0fcde92d8408f93</cites><orcidid>0000-0003-0965-349X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37451818$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Aoran</creatorcontrib><creatorcontrib>Xu, Tianhua</creatorcontrib><creatorcontrib>Lu, Xiaomei</creatorcontrib><creatorcontrib>Ma, Ling</creatorcontrib><creatorcontrib>Ma, Haiying</creatorcontrib><creatorcontrib>Yu, Yanqiu</creatorcontrib><creatorcontrib>Yao, Li</creatorcontrib><title>Shh–Gli2–Runx2 inhibits vascular calcification</title><title>Nephrology, dialysis, transplantation</title><addtitle>Nephrol Dial Transplant</addtitle><description>ABSTRACT
Background
In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC.
Methods
Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC.
Results
Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B.
Conclusions
Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.
Graphical Abstract
Graphical Abstract</description><subject>Adenine</subject><subject>Animals</subject><subject>Core Binding Factor Alpha 1 Subunit - genetics</subject><subject>Core Binding Factor Alpha 1 Subunit - metabolism</subject><subject>Hedgehog Proteins - genetics</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Hedgehog Proteins - pharmacology</subject><subject>Humans</subject><subject>Mice</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Phosphorus - metabolism</subject><subject>Renal Insufficiency, Chronic - pathology</subject><subject>Vascular Calcification - etiology</subject><subject>Vascular Calcification - metabolism</subject><subject>Vascular Calcification - prevention & control</subject><issn>0931-0509</issn><issn>1460-2385</issn><issn>1460-2385</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtKAzEUhoMotl5W7qUrEWTsSTKZnFlK0SoUBC_rkOZiI9OZOpkR3fkOvqFPYqTVpat_cT4-Dh8hRxTOKZR8XNtu_OS1pYXYIkOaF5AxjmKbDNOVZiCgHJC9GJ8BoGRS7pIBl7mgSHFI2P1i8fXxOa0CS3PX129sFOpFmIcujl51NH2l25HRlQk-GN2Fpj4gO15X0R1udp88Xl0-TK6z2e30ZnIxywyT2GXoAQzHUuvSopGG2cIyL4RE5iBnaNI3gjNJDfpCAkgL3lhXMos5oC_5Pjlde1dt89K72KlliMZVla5d00fFkCMTtMgxoWdr1LRNjK3zatWGpW7fFQX1E0mlSGoTKdHHG3E_Xzr7x_5WScDJGmj61b-mb__WcM4</recordid><startdate>20240131</startdate><enddate>20240131</enddate><creator>Huang, Aoran</creator><creator>Xu, Tianhua</creator><creator>Lu, Xiaomei</creator><creator>Ma, Ling</creator><creator>Ma, Haiying</creator><creator>Yu, Yanqiu</creator><creator>Yao, Li</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0965-349X</orcidid></search><sort><creationdate>20240131</creationdate><title>Shh–Gli2–Runx2 inhibits vascular calcification</title><author>Huang, Aoran ; Xu, Tianhua ; Lu, Xiaomei ; Ma, Ling ; Ma, Haiying ; Yu, Yanqiu ; Yao, Li</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c278t-8f00c389aa9d8c7c2d6d2f55782e0428c00953271c8f67007d0fcde92d8408f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adenine</topic><topic>Animals</topic><topic>Core Binding Factor Alpha 1 Subunit - genetics</topic><topic>Core Binding Factor Alpha 1 Subunit - metabolism</topic><topic>Hedgehog Proteins - genetics</topic><topic>Hedgehog Proteins - metabolism</topic><topic>Hedgehog Proteins - pharmacology</topic><topic>Humans</topic><topic>Mice</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Phosphorus - metabolism</topic><topic>Renal Insufficiency, Chronic - pathology</topic><topic>Vascular Calcification - etiology</topic><topic>Vascular Calcification - metabolism</topic><topic>Vascular Calcification - prevention & control</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Aoran</creatorcontrib><creatorcontrib>Xu, Tianhua</creatorcontrib><creatorcontrib>Lu, Xiaomei</creatorcontrib><creatorcontrib>Ma, Ling</creatorcontrib><creatorcontrib>Ma, Haiying</creatorcontrib><creatorcontrib>Yu, Yanqiu</creatorcontrib><creatorcontrib>Yao, Li</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Nephrology, dialysis, transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Aoran</au><au>Xu, Tianhua</au><au>Lu, Xiaomei</au><au>Ma, Ling</au><au>Ma, Haiying</au><au>Yu, Yanqiu</au><au>Yao, Li</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Shh–Gli2–Runx2 inhibits vascular calcification</atitle><jtitle>Nephrology, dialysis, transplantation</jtitle><addtitle>Nephrol Dial Transplant</addtitle><date>2024-01-31</date><risdate>2024</risdate><volume>39</volume><issue>2</issue><spage>305</spage><epage>316</epage><pages>305-316</pages><issn>0931-0509</issn><issn>1460-2385</issn><eissn>1460-2385</eissn><abstract>ABSTRACT
Background
In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC.
Methods
Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC.
Results
Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B.
Conclusions
Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.
Graphical Abstract
Graphical Abstract</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>37451818</pmid><doi>10.1093/ndt/gfad165</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-0965-349X</orcidid></addata></record> |
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| subjects | Adenine Animals Core Binding Factor Alpha 1 Subunit - genetics Core Binding Factor Alpha 1 Subunit - metabolism Hedgehog Proteins - genetics Hedgehog Proteins - metabolism Hedgehog Proteins - pharmacology Humans Mice Myocytes, Smooth Muscle - metabolism Phosphorus - metabolism Renal Insufficiency, Chronic - pathology Vascular Calcification - etiology Vascular Calcification - metabolism Vascular Calcification - prevention & control |
| title | Shh–Gli2–Runx2 inhibits vascular calcification |
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