Aberrant splicing of Ca V 1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia
Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca 1.2 calcium channel is one primary pathway for Ca influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca 1.2 functions under hyp...
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creator | Hou, Wei Yin, Shumin Li, Pengpeng Zhang, Ludan Chen, Tiange Qin, Dongxia Mustafa, Atta Ul Liu, Caijie Song, Miaomiao Qiu, Cheng Xiong, Xiaoqing Wang, Juejin |
description | Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca
1.2 calcium channel is one primary pathway for Ca
influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca
1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K
-induced arterial constriction and Ca
1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K
-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and Ca
1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, Ca
1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of Ca
1.2 channels in VSMCs and MAs. Notably, GS increases K
-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates Ca
1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications. |
format | Article |
fullrecord | <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmed_primary_38575795</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>38575795</sourcerecordid><originalsourceid>FETCH-pubmed_primary_385757953</originalsourceid><addsrcrecordid>eNqFjtFqwkAQRRehVKv9BZkfsGSjafSxSKXPpfgqs7MTnbLZhNkNND_Q79ZC-9ynw4XD5UzMzG7KYrUrajs1Dyl9FoWttuXzvZmut1Vd1btqZr5fHKtizJD6ICTxDF0De4Qj2KcSCAPJ0AJdMEYOINEPxB7cCJ5JGdNtvLum-7LA8SYRJ0DNrIIBqIspq1CWLoIf9OfdCzrOQnAZe9ZzGIlbwYW5azAkfvzl3CwPrx_7t1U_uJb9qVdpUcfTX_j6X-EKb-BQGA</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Aberrant splicing of Ca V 1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia</title><source>MEDLINE</source><source>SpringerNature Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Hou, Wei ; Yin, Shumin ; Li, Pengpeng ; Zhang, Ludan ; Chen, Tiange ; Qin, Dongxia ; Mustafa, Atta Ul ; Liu, Caijie ; Song, Miaomiao ; Qiu, Cheng ; Xiong, Xiaoqing ; Wang, Juejin</creator><creatorcontrib>Hou, Wei ; Yin, Shumin ; Li, Pengpeng ; Zhang, Ludan ; Chen, Tiange ; Qin, Dongxia ; Mustafa, Atta Ul ; Liu, Caijie ; Song, Miaomiao ; Qiu, Cheng ; Xiong, Xiaoqing ; Wang, Juejin</creatorcontrib><description>Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca
1.2 calcium channel is one primary pathway for Ca
influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca
1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K
-induced arterial constriction and Ca
1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K
-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and Ca
1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, Ca
1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of Ca
1.2 channels in VSMCs and MAs. Notably, GS increases K
-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates Ca
1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.</description><identifier>EISSN: 1420-9071</identifier><identifier>PMID: 38575795</identifier><language>eng</language><publisher>Switzerland</publisher><subject>Animals ; Calcium - metabolism ; Calcium Channels, L-Type - genetics ; Calcium Channels, L-Type - metabolism ; Constriction ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - genetics ; Diabetes Mellitus, Experimental - metabolism ; Diabetic Angiopathies - metabolism ; Glucose - metabolism ; Hyperglycemia - genetics ; Hyperglycemia - metabolism ; Muscle, Smooth, Vascular - metabolism ; Myocytes, Smooth Muscle - metabolism ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Cellular and molecular life sciences : CMLS, 2024-04, Vol.81 (1), p.164</ispartof><rights>2024. The Author(s).</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0003-4921-5451</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38575795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hou, Wei</creatorcontrib><creatorcontrib>Yin, Shumin</creatorcontrib><creatorcontrib>Li, Pengpeng</creatorcontrib><creatorcontrib>Zhang, Ludan</creatorcontrib><creatorcontrib>Chen, Tiange</creatorcontrib><creatorcontrib>Qin, Dongxia</creatorcontrib><creatorcontrib>Mustafa, Atta Ul</creatorcontrib><creatorcontrib>Liu, Caijie</creatorcontrib><creatorcontrib>Song, Miaomiao</creatorcontrib><creatorcontrib>Qiu, Cheng</creatorcontrib><creatorcontrib>Xiong, Xiaoqing</creatorcontrib><creatorcontrib>Wang, Juejin</creatorcontrib><title>Aberrant splicing of Ca V 1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell Mol Life Sci</addtitle><description>Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca
1.2 calcium channel is one primary pathway for Ca
influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca
1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K
-induced arterial constriction and Ca
1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K
-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and Ca
1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, Ca
1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of Ca
1.2 channels in VSMCs and MAs. Notably, GS increases K
-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates Ca
1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.</description><subject>Animals</subject><subject>Calcium - metabolism</subject><subject>Calcium Channels, L-Type - genetics</subject><subject>Calcium Channels, L-Type - metabolism</subject><subject>Constriction</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - genetics</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetic Angiopathies - metabolism</subject><subject>Glucose - metabolism</subject><subject>Hyperglycemia - genetics</subject><subject>Hyperglycemia - metabolism</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>1420-9071</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjtFqwkAQRRehVKv9BZkfsGSjafSxSKXPpfgqs7MTnbLZhNkNND_Q79ZC-9ynw4XD5UzMzG7KYrUrajs1Dyl9FoWttuXzvZmut1Vd1btqZr5fHKtizJD6ICTxDF0De4Qj2KcSCAPJ0AJdMEYOINEPxB7cCJ5JGdNtvLum-7LA8SYRJ0DNrIIBqIspq1CWLoIf9OfdCzrOQnAZe9ZzGIlbwYW5azAkfvzl3CwPrx_7t1U_uJb9qVdpUcfTX_j6X-EKb-BQGA</recordid><startdate>20240404</startdate><enddate>20240404</enddate><creator>Hou, Wei</creator><creator>Yin, Shumin</creator><creator>Li, Pengpeng</creator><creator>Zhang, Ludan</creator><creator>Chen, Tiange</creator><creator>Qin, Dongxia</creator><creator>Mustafa, Atta Ul</creator><creator>Liu, Caijie</creator><creator>Song, Miaomiao</creator><creator>Qiu, Cheng</creator><creator>Xiong, Xiaoqing</creator><creator>Wang, Juejin</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0003-4921-5451</orcidid></search><sort><creationdate>20240404</creationdate><title>Aberrant splicing of Ca V 1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia</title><author>Hou, Wei ; Yin, Shumin ; Li, Pengpeng ; Zhang, Ludan ; Chen, Tiange ; Qin, Dongxia ; Mustafa, Atta Ul ; Liu, Caijie ; Song, Miaomiao ; Qiu, Cheng ; Xiong, Xiaoqing ; Wang, Juejin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_385757953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Calcium - metabolism</topic><topic>Calcium Channels, L-Type - genetics</topic><topic>Calcium Channels, L-Type - metabolism</topic><topic>Constriction</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetes Mellitus, Experimental - genetics</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetic Angiopathies - metabolism</topic><topic>Glucose - metabolism</topic><topic>Hyperglycemia - genetics</topic><topic>Hyperglycemia - metabolism</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hou, Wei</creatorcontrib><creatorcontrib>Yin, Shumin</creatorcontrib><creatorcontrib>Li, Pengpeng</creatorcontrib><creatorcontrib>Zhang, Ludan</creatorcontrib><creatorcontrib>Chen, Tiange</creatorcontrib><creatorcontrib>Qin, Dongxia</creatorcontrib><creatorcontrib>Mustafa, Atta Ul</creatorcontrib><creatorcontrib>Liu, Caijie</creatorcontrib><creatorcontrib>Song, Miaomiao</creatorcontrib><creatorcontrib>Qiu, Cheng</creatorcontrib><creatorcontrib>Xiong, Xiaoqing</creatorcontrib><creatorcontrib>Wang, Juejin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cellular and molecular life sciences : CMLS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hou, Wei</au><au>Yin, Shumin</au><au>Li, Pengpeng</au><au>Zhang, Ludan</au><au>Chen, Tiange</au><au>Qin, Dongxia</au><au>Mustafa, Atta Ul</au><au>Liu, Caijie</au><au>Song, Miaomiao</au><au>Qiu, Cheng</au><au>Xiong, Xiaoqing</au><au>Wang, Juejin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aberrant splicing of Ca V 1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia</atitle><jtitle>Cellular and molecular life sciences : CMLS</jtitle><addtitle>Cell Mol Life Sci</addtitle><date>2024-04-04</date><risdate>2024</risdate><volume>81</volume><issue>1</issue><spage>164</spage><pages>164-</pages><eissn>1420-9071</eissn><abstract>Diabetic hyperglycemia induces dysfunctions of arterial smooth muscle, leading to diabetic vascular complications. The Ca
1.2 calcium channel is one primary pathway for Ca
influx, which initiates vasoconstriction. However, the long-term regulation mechanism(s) for vascular Ca
1.2 functions under hyperglycemic condition remains unknown. Here, Sprague-Dawley rats fed with high-fat diet in combination with low dose streptozotocin and Goto-Kakizaki (GK) rats were used as diabetic models. Isolated mesenteric arteries (MAs) and vascular smooth muscle cells (VSMCs) from rat models were used to assess K
-induced arterial constriction and Ca
1.2 channel functions using vascular myograph and whole-cell patch clamp, respectively. K
-induced vasoconstriction is persistently enhanced in the MAs from diabetic rats, and Ca
1.2 alternative spliced exon 9* is increased, while exon 33 is decreased in rat diabetic arteries. Furthermore, Ca
1.2 channels exhibit hyperpolarized current-voltage and activation curve in VSMCs from diabetic rats, which facilitates the channel function. Unexpectedly, the application of glycated serum (GS), mimicking advanced glycation end-products (AGEs), but not glucose, downregulates the expression of the splicing factor Rbfox1 in VSMCs. Moreover, GS application or Rbfox1 knockdown dynamically regulates alternative exons 9* and 33, leading to facilitated functions of Ca
1.2 channels in VSMCs and MAs. Notably, GS increases K
-induced intracellular calcium concentration of VSMCs and the vasoconstriction of MAs. These results reveal that AGEs, not glucose, long-termly regulates Ca
1.2 alternative splicing events by decreasing Rbfox1 expression, thereby enhancing channel functions and increasing vasoconstriction under diabetic hyperglycemia. This study identifies the specific molecular mechanism for enhanced vasoconstriction under hyperglycemia, providing a potential target for managing diabetic vascular complications.</abstract><cop>Switzerland</cop><pmid>38575795</pmid><orcidid>https://orcid.org/0000-0003-4921-5451</orcidid></addata></record> |
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subjects | Animals Calcium - metabolism Calcium Channels, L-Type - genetics Calcium Channels, L-Type - metabolism Constriction Diabetes Mellitus, Experimental - complications Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - metabolism Diabetic Angiopathies - metabolism Glucose - metabolism Hyperglycemia - genetics Hyperglycemia - metabolism Muscle, Smooth, Vascular - metabolism Myocytes, Smooth Muscle - metabolism Rats Rats, Sprague-Dawley |
title | Aberrant splicing of Ca V 1.2 calcium channel induced by decreased Rbfox1 enhances arterial constriction during diabetic hyperglycemia |
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