Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice
Arterial medial calcification (AMC) involves an increased small extracellular vesicle (sEV) secretion and apatite calcium precipitation in the arterial wall. The mechanisms mediating AMC remain poorly understood. In the present study, smooth muscle-specific acid ceramidase (Ac) gene knockout mice (...
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| description | Arterial medial calcification (AMC) involves an increased small extracellular vesicle (sEV) secretion and apatite calcium precipitation in the arterial wall. The mechanisms mediating AMC remain poorly understood. In the present study, smooth muscle-specific acid ceramidase (Ac) gene knockout mice (
Asah1
fl/fl
/SM
Cre
) were used to demonstrate the role of lysosomal ceramide signaling pathway in AMC.
Asah1
fl/fl
/SM
Cre
mice were found to have more severe AMC in both aorta and coronary arteries compared to their littermates (
Asah1
fl/fl
/SM
wt
and WT/WT mice) after receiving a high dose vitamin D. These mice also had pronounced upregulation of osteopontin and RUNX2 (osteogenic markers), CD63, AnX2 (sEV markers) and ALP expression (mineralization marker) in the arterial media. In cultured coronary arterial smooth muscle cells (CASMCs) from
Asah1
fl/fl
/SM
Cre
mice, high dose of P
i
led to a significantly increased calcium deposition, phenotypic change and sEV secretion compared to WT CASMCs, which was associated with reduced lysosome-multivesicular body (MVB) interaction. Also, GW4869, sEV release inhibitor decreased sEV secretion and calcification in these cells. Lysosomal transient receptor potential mucolipin 1 (TRPML1) channels regulating lysosome interaction with MVBs were found remarkably inhibited in
Asah1
fl/fl
/SM
Cre
CASMCs as shown by GCaMP3 Ca
2+
imaging and Port-a-Patch patch clamping of lysosomes. Lysosomal Ac in SMCs controls sEV release by regulating lysosomal TRPML1 channel activity and lysosome-MVB interaction, which importantly contributes to phenotypic transition and AMC. |
| doi_str_mv | 10.1038/s41598-020-58568-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6997457</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2350325067</sourcerecordid><originalsourceid>FETCH-LOGICAL-c511t-114e8a541d349fb63b38e00a0303cbf7f5c4de0361aa21c64356ad4ff3e608413</originalsourceid><addsrcrecordid>eNp9kc9uEzEQxi0EolXbF-CALHFe6r-b3QtSFKUFtVElClytiXc26-LYwd5F8AC8N05TSrngy1j6vvnNjD5CXnH2ljPZnGfFddtUTLBKN7puKv2MHAumdCWkEM-f_I_IWc53rDwtWsXbl-RICsa1bNtj8mueRkwOPF1hty8L8Nb1zsLoYqDjkOK0GegyDBAsdjRvwXu6_DEmsOj95CHRL5id9Ug_okfISF2gt9sYx4GuplyE6naH90w6zzBweokB6VWI9mucRrpyFk_Jix58xrOHekI-Xyw_Ld5X1zeXHxbz68pqzseKc4UNaMU7qdp-Xcu1bJAxYJJJu-5nvbaqQyZrDiC4rZXUNXSq7yXWrFFcnpB3B-5uWm-xsxjKHd7skttC-mkiOPOvEtxgNvG7qdt2pvSsAN48AFL8NmEezV2cUig7GyE1k0Kzeu8SB5dNMeeE_eMEzsw-PXNIz5T0zH16Rpem1093e2z5k1UxyIMhFylsMP2d_R_sb1ubpxk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2350325067</pqid></control><display><type>article</type><title>Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Springer Nature OA Free Journals</source><source>Nature Free</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Bhat, Owais M. ; Li, Guangbi ; Yuan, Xinxu ; Huang, Dandan ; Gulbins, Erich ; Kukreja, Rakesh C. ; Li, Pin-Lan</creator><creatorcontrib>Bhat, Owais M. ; Li, Guangbi ; Yuan, Xinxu ; Huang, Dandan ; Gulbins, Erich ; Kukreja, Rakesh C. ; Li, Pin-Lan</creatorcontrib><description>Arterial medial calcification (AMC) involves an increased small extracellular vesicle (sEV) secretion and apatite calcium precipitation in the arterial wall. The mechanisms mediating AMC remain poorly understood. In the present study, smooth muscle-specific acid ceramidase (Ac) gene knockout mice (
Asah1
fl/fl
/SM
Cre
) were used to demonstrate the role of lysosomal ceramide signaling pathway in AMC.
Asah1
fl/fl
/SM
Cre
mice were found to have more severe AMC in both aorta and coronary arteries compared to their littermates (
Asah1
fl/fl
/SM
wt
and WT/WT mice) after receiving a high dose vitamin D. These mice also had pronounced upregulation of osteopontin and RUNX2 (osteogenic markers), CD63, AnX2 (sEV markers) and ALP expression (mineralization marker) in the arterial media. In cultured coronary arterial smooth muscle cells (CASMCs) from
Asah1
fl/fl
/SM
Cre
mice, high dose of P
i
led to a significantly increased calcium deposition, phenotypic change and sEV secretion compared to WT CASMCs, which was associated with reduced lysosome-multivesicular body (MVB) interaction. Also, GW4869, sEV release inhibitor decreased sEV secretion and calcification in these cells. Lysosomal transient receptor potential mucolipin 1 (TRPML1) channels regulating lysosome interaction with MVBs were found remarkably inhibited in
Asah1
fl/fl
/SM
Cre
CASMCs as shown by GCaMP3 Ca
2+
imaging and Port-a-Patch patch clamping of lysosomes. Lysosomal Ac in SMCs controls sEV release by regulating lysosomal TRPML1 channel activity and lysosome-MVB interaction, which importantly contributes to phenotypic transition and AMC.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-58568-5</identifier><identifier>PMID: 32015399</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/109 ; 13/51 ; 14/1 ; 14/19 ; 14/63 ; 631/45/881 ; 631/80/2373 ; 64/110 ; 9/74 ; Acid Ceramidase - genetics ; Acid Ceramidase - metabolism ; Animals ; Aorta ; Aorta - metabolism ; Aorta - pathology ; Apatite ; Calcification ; Calcium ; Calcium imaging ; Calcium Signaling ; Cbfa-1 protein ; CD63 antigen ; Cells, Cultured ; Ceramidase ; Ceramide ; Channel gating ; Coronary artery ; Coronary Vessels - metabolism ; Coronary Vessels - pathology ; Disease Models, Animal ; Extracellular Vesicles - metabolism ; Extracellular Vesicles - pathology ; Farber Lipogranulomatosis - genetics ; Farber Lipogranulomatosis - metabolism ; Humanities and Social Sciences ; Lysosomes ; Lysosomes - metabolism ; Male ; Metabolic Networks and Pathways ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mineralization ; Models, Cardiovascular ; multidisciplinary ; Muscle, Smooth, Vascular - metabolism ; Muscle, Smooth, Vascular - pathology ; Myocytes, Smooth Muscle - metabolism ; Myocytes, Smooth Muscle - pathology ; Osteopontin ; Rodents ; Science ; Science (multidisciplinary) ; Secretion ; Signal transduction ; Smooth muscle ; Sphingolipids - metabolism ; Transient Receptor Potential Channels - agonists ; Transient Receptor Potential Channels - metabolism ; Transient receptor potential proteins ; Vascular Calcification - genetics ; Vascular Calcification - metabolism ; Vascular Calcification - pathology ; Vitamin D</subject><ispartof>Scientific reports, 2020-02, Vol.10 (1), p.1645, Article 1645</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-114e8a541d349fb63b38e00a0303cbf7f5c4de0361aa21c64356ad4ff3e608413</citedby><cites>FETCH-LOGICAL-c511t-114e8a541d349fb63b38e00a0303cbf7f5c4de0361aa21c64356ad4ff3e608413</cites><orcidid>0000-0002-3117-1342</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997457/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997457/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32015399$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bhat, Owais M.</creatorcontrib><creatorcontrib>Li, Guangbi</creatorcontrib><creatorcontrib>Yuan, Xinxu</creatorcontrib><creatorcontrib>Huang, Dandan</creatorcontrib><creatorcontrib>Gulbins, Erich</creatorcontrib><creatorcontrib>Kukreja, Rakesh C.</creatorcontrib><creatorcontrib>Li, Pin-Lan</creatorcontrib><title>Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Arterial medial calcification (AMC) involves an increased small extracellular vesicle (sEV) secretion and apatite calcium precipitation in the arterial wall. The mechanisms mediating AMC remain poorly understood. In the present study, smooth muscle-specific acid ceramidase (Ac) gene knockout mice (
Asah1
fl/fl
/SM
Cre
) were used to demonstrate the role of lysosomal ceramide signaling pathway in AMC.
Asah1
fl/fl
/SM
Cre
mice were found to have more severe AMC in both aorta and coronary arteries compared to their littermates (
Asah1
fl/fl
/SM
wt
and WT/WT mice) after receiving a high dose vitamin D. These mice also had pronounced upregulation of osteopontin and RUNX2 (osteogenic markers), CD63, AnX2 (sEV markers) and ALP expression (mineralization marker) in the arterial media. In cultured coronary arterial smooth muscle cells (CASMCs) from
Asah1
fl/fl
/SM
Cre
mice, high dose of P
i
led to a significantly increased calcium deposition, phenotypic change and sEV secretion compared to WT CASMCs, which was associated with reduced lysosome-multivesicular body (MVB) interaction. Also, GW4869, sEV release inhibitor decreased sEV secretion and calcification in these cells. Lysosomal transient receptor potential mucolipin 1 (TRPML1) channels regulating lysosome interaction with MVBs were found remarkably inhibited in
Asah1
fl/fl
/SM
Cre
CASMCs as shown by GCaMP3 Ca
2+
imaging and Port-a-Patch patch clamping of lysosomes. Lysosomal Ac in SMCs controls sEV release by regulating lysosomal TRPML1 channel activity and lysosome-MVB interaction, which importantly contributes to phenotypic transition and AMC.</description><subject>13/1</subject><subject>13/106</subject><subject>13/109</subject><subject>13/51</subject><subject>14/1</subject><subject>14/19</subject><subject>14/63</subject><subject>631/45/881</subject><subject>631/80/2373</subject><subject>64/110</subject><subject>9/74</subject><subject>Acid Ceramidase - genetics</subject><subject>Acid Ceramidase - metabolism</subject><subject>Animals</subject><subject>Aorta</subject><subject>Aorta - metabolism</subject><subject>Aorta - pathology</subject><subject>Apatite</subject><subject>Calcification</subject><subject>Calcium</subject><subject>Calcium imaging</subject><subject>Calcium Signaling</subject><subject>Cbfa-1 protein</subject><subject>CD63 antigen</subject><subject>Cells, Cultured</subject><subject>Ceramidase</subject><subject>Ceramide</subject><subject>Channel gating</subject><subject>Coronary artery</subject><subject>Coronary Vessels - metabolism</subject><subject>Coronary Vessels - pathology</subject><subject>Disease Models, Animal</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Extracellular Vesicles - pathology</subject><subject>Farber Lipogranulomatosis - genetics</subject><subject>Farber Lipogranulomatosis - metabolism</subject><subject>Humanities and Social Sciences</subject><subject>Lysosomes</subject><subject>Lysosomes - metabolism</subject><subject>Male</subject><subject>Metabolic Networks and Pathways</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mineralization</subject><subject>Models, Cardiovascular</subject><subject>multidisciplinary</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Muscle, Smooth, Vascular - pathology</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Myocytes, Smooth Muscle - pathology</subject><subject>Osteopontin</subject><subject>Rodents</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Secretion</subject><subject>Signal transduction</subject><subject>Smooth muscle</subject><subject>Sphingolipids - metabolism</subject><subject>Transient Receptor Potential Channels - agonists</subject><subject>Transient Receptor Potential Channels - metabolism</subject><subject>Transient receptor potential proteins</subject><subject>Vascular Calcification - genetics</subject><subject>Vascular Calcification - metabolism</subject><subject>Vascular Calcification - pathology</subject><subject>Vitamin D</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc9uEzEQxi0EolXbF-CALHFe6r-b3QtSFKUFtVElClytiXc26-LYwd5F8AC8N05TSrngy1j6vvnNjD5CXnH2ljPZnGfFddtUTLBKN7puKv2MHAumdCWkEM-f_I_IWc53rDwtWsXbl-RICsa1bNtj8mueRkwOPF1hty8L8Nb1zsLoYqDjkOK0GegyDBAsdjRvwXu6_DEmsOj95CHRL5id9Ug_okfISF2gt9sYx4GuplyE6naH90w6zzBweokB6VWI9mucRrpyFk_Jix58xrOHekI-Xyw_Ld5X1zeXHxbz68pqzseKc4UNaMU7qdp-Xcu1bJAxYJJJu-5nvbaqQyZrDiC4rZXUNXSq7yXWrFFcnpB3B-5uWm-xsxjKHd7skttC-mkiOPOvEtxgNvG7qdt2pvSsAN48AFL8NmEezV2cUig7GyE1k0Kzeu8SB5dNMeeE_eMEzsw-PXNIz5T0zH16Rpem1093e2z5k1UxyIMhFylsMP2d_R_sb1ubpxk</recordid><startdate>20200203</startdate><enddate>20200203</enddate><creator>Bhat, Owais M.</creator><creator>Li, Guangbi</creator><creator>Yuan, Xinxu</creator><creator>Huang, Dandan</creator><creator>Gulbins, Erich</creator><creator>Kukreja, Rakesh C.</creator><creator>Li, Pin-Lan</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3117-1342</orcidid></search><sort><creationdate>20200203</creationdate><title>Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice</title><author>Bhat, Owais M. ; Li, Guangbi ; Yuan, Xinxu ; Huang, Dandan ; Gulbins, Erich ; Kukreja, Rakesh C. ; Li, Pin-Lan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-114e8a541d349fb63b38e00a0303cbf7f5c4de0361aa21c64356ad4ff3e608413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/109</topic><topic>13/51</topic><topic>14/1</topic><topic>14/19</topic><topic>14/63</topic><topic>631/45/881</topic><topic>631/80/2373</topic><topic>64/110</topic><topic>9/74</topic><topic>Acid Ceramidase - genetics</topic><topic>Acid Ceramidase - metabolism</topic><topic>Animals</topic><topic>Aorta</topic><topic>Aorta - metabolism</topic><topic>Aorta - pathology</topic><topic>Apatite</topic><topic>Calcification</topic><topic>Calcium</topic><topic>Calcium imaging</topic><topic>Calcium Signaling</topic><topic>Cbfa-1 protein</topic><topic>CD63 antigen</topic><topic>Cells, Cultured</topic><topic>Ceramidase</topic><topic>Ceramide</topic><topic>Channel gating</topic><topic>Coronary artery</topic><topic>Coronary Vessels - metabolism</topic><topic>Coronary Vessels - pathology</topic><topic>Disease Models, Animal</topic><topic>Extracellular Vesicles - metabolism</topic><topic>Extracellular Vesicles - pathology</topic><topic>Farber Lipogranulomatosis - genetics</topic><topic>Farber Lipogranulomatosis - metabolism</topic><topic>Humanities and Social Sciences</topic><topic>Lysosomes</topic><topic>Lysosomes - metabolism</topic><topic>Male</topic><topic>Metabolic Networks and Pathways</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mineralization</topic><topic>Models, Cardiovascular</topic><topic>multidisciplinary</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Muscle, Smooth, Vascular - pathology</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Myocytes, Smooth Muscle - pathology</topic><topic>Osteopontin</topic><topic>Rodents</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Secretion</topic><topic>Signal transduction</topic><topic>Smooth muscle</topic><topic>Sphingolipids - metabolism</topic><topic>Transient Receptor Potential Channels - agonists</topic><topic>Transient Receptor Potential Channels - metabolism</topic><topic>Transient receptor potential proteins</topic><topic>Vascular Calcification - genetics</topic><topic>Vascular Calcification - metabolism</topic><topic>Vascular Calcification - pathology</topic><topic>Vitamin D</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bhat, Owais M.</creatorcontrib><creatorcontrib>Li, Guangbi</creatorcontrib><creatorcontrib>Yuan, Xinxu</creatorcontrib><creatorcontrib>Huang, Dandan</creatorcontrib><creatorcontrib>Gulbins, Erich</creatorcontrib><creatorcontrib>Kukreja, Rakesh C.</creatorcontrib><creatorcontrib>Li, Pin-Lan</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bhat, Owais M.</au><au>Li, Guangbi</au><au>Yuan, Xinxu</au><au>Huang, Dandan</au><au>Gulbins, Erich</au><au>Kukreja, Rakesh C.</au><au>Li, Pin-Lan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-02-03</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>1645</spage><pages>1645-</pages><artnum>1645</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Arterial medial calcification (AMC) involves an increased small extracellular vesicle (sEV) secretion and apatite calcium precipitation in the arterial wall. The mechanisms mediating AMC remain poorly understood. In the present study, smooth muscle-specific acid ceramidase (Ac) gene knockout mice (
Asah1
fl/fl
/SM
Cre
) were used to demonstrate the role of lysosomal ceramide signaling pathway in AMC.
Asah1
fl/fl
/SM
Cre
mice were found to have more severe AMC in both aorta and coronary arteries compared to their littermates (
Asah1
fl/fl
/SM
wt
and WT/WT mice) after receiving a high dose vitamin D. These mice also had pronounced upregulation of osteopontin and RUNX2 (osteogenic markers), CD63, AnX2 (sEV markers) and ALP expression (mineralization marker) in the arterial media. In cultured coronary arterial smooth muscle cells (CASMCs) from
Asah1
fl/fl
/SM
Cre
mice, high dose of P
i
led to a significantly increased calcium deposition, phenotypic change and sEV secretion compared to WT CASMCs, which was associated with reduced lysosome-multivesicular body (MVB) interaction. Also, GW4869, sEV release inhibitor decreased sEV secretion and calcification in these cells. Lysosomal transient receptor potential mucolipin 1 (TRPML1) channels regulating lysosome interaction with MVBs were found remarkably inhibited in
Asah1
fl/fl
/SM
Cre
CASMCs as shown by GCaMP3 Ca
2+
imaging and Port-a-Patch patch clamping of lysosomes. Lysosomal Ac in SMCs controls sEV release by regulating lysosomal TRPML1 channel activity and lysosome-MVB interaction, which importantly contributes to phenotypic transition and AMC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32015399</pmid><doi>10.1038/s41598-020-58568-5</doi><orcidid>https://orcid.org/0000-0002-3117-1342</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Scientific reports, 2020-02, Vol.10 (1), p.1645, Article 1645 |
| issn | 2045-2322 2045-2322 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6997457 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 13/1 13/106 13/109 13/51 14/1 14/19 14/63 631/45/881 631/80/2373 64/110 9/74 Acid Ceramidase - genetics Acid Ceramidase - metabolism Animals Aorta Aorta - metabolism Aorta - pathology Apatite Calcification Calcium Calcium imaging Calcium Signaling Cbfa-1 protein CD63 antigen Cells, Cultured Ceramidase Ceramide Channel gating Coronary artery Coronary Vessels - metabolism Coronary Vessels - pathology Disease Models, Animal Extracellular Vesicles - metabolism Extracellular Vesicles - pathology Farber Lipogranulomatosis - genetics Farber Lipogranulomatosis - metabolism Humanities and Social Sciences Lysosomes Lysosomes - metabolism Male Metabolic Networks and Pathways Mice Mice, Inbred C57BL Mice, Knockout Mineralization Models, Cardiovascular multidisciplinary Muscle, Smooth, Vascular - metabolism Muscle, Smooth, Vascular - pathology Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Osteopontin Rodents Science Science (multidisciplinary) Secretion Signal transduction Smooth muscle Sphingolipids - metabolism Transient Receptor Potential Channels - agonists Transient Receptor Potential Channels - metabolism Transient receptor potential proteins Vascular Calcification - genetics Vascular Calcification - metabolism Vascular Calcification - pathology Vitamin D |
| title | Arterial Medial Calcification through Enhanced small Extracellular Vesicle Release in Smooth Muscle-Specific Asah1 Gene Knockout Mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T14%3A57%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Arterial%20Medial%20Calcification%20through%20Enhanced%20small%20Extracellular%20Vesicle%20Release%20in%20Smooth%20Muscle-Specific%20Asah1%20Gene%20Knockout%20Mice&rft.jtitle=Scientific%20reports&rft.au=Bhat,%20Owais%20M.&rft.date=2020-02-03&rft.volume=10&rft.issue=1&rft.spage=1645&rft.pages=1645-&rft.artnum=1645&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-020-58568-5&rft_dat=%3Cproquest_pubme%3E2350325067%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2350325067&rft_id=info:pmid/32015399&rfr_iscdi=true |