Increased iNOS activity in vascular smooth muscle cells from diabetic rats: potential role of Ca(2+)/calmodulin-dependent protein kinase II delta 2 (CaMKIIδ(2))
Inducible nitric oxide synthase (iNOS) expression may be increased by cytokine plasma levels contributing to vascular damage in diabetes. Besides transcriptional regulation, Ca(2+)/CaMKII may play a role in post-translationally controlled iNOS activity. We accordingly investigated the involvement of...
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| Veröffentlicht in: | Atherosclerosis 2013-01, Vol.226 (1), p.88-94 |
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| container_title | Atherosclerosis |
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| creator | Di Pietro, Natalia Di Tomo, Pamela Di Silvestre, Sara Giardinelli, Annalisa Pipino, Caterina Morabito, Caterina Formoso, Gloria Mariggiò, Maria Addolorata Pandolfi, Assunta |
| description | Inducible nitric oxide synthase (iNOS) expression may be increased by cytokine plasma levels contributing to vascular damage in diabetes. Besides transcriptional regulation, Ca(2+)/CaMKII may play a role in post-translationally controlled iNOS activity. We accordingly investigated the involvement of the Ca(2+)/CaMKIIδ(2) signaling pathway in regulating lipopolysaccharide (LPS)-induced iNOS activity in cultured aortic vascular smooth muscle cells (VSMCs) from diabetic rats.
VSMCs obtained from 10 diabetic rats (DR) and 10 control rats (CR) were stimulated with 20 μg/ml LPS. After 24 h, iNOS protein levels were 1.37 fold increased in DR- vs CR-VSMCs (p |
| doi_str_mv | 10.1016/j.atherosclerosis.2012.10.062 |
| format | Article |
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VSMCs obtained from 10 diabetic rats (DR) and 10 control rats (CR) were stimulated with 20 μg/ml LPS. After 24 h, iNOS protein levels were 1.37 fold increased in DR- vs CR-VSMCs (p < 0.05; Western Blot), while iNOS activity (conversion l-((3)H)-arginine into l-((3)H)-citrulline) and intracellular nitrotyrosine levels (immunofluorescence) were about 2.7 fold greater in DR- than in CR-VSMCs. Interestingly, LPS increased intracellular Ca(2+) levels (Fluorescence video imaging) more markedly in DR- than in CR-VSMCs. This was associated with CaMKII activation by phosphorylation, a decreased amount of co-immunoprecipitating iNOS/CaMKIIδ(2) (Western Blot) and increased iNOS activity. The CaMKII inhibitor KN-93 abolished all the LPS-effects.
These results indicate that the Ca(2+)/CaMKIIδ(2) signaling pathway may be an important regulator of iNOS activity in diabetes, and hence contribute to the potential development of innovative therapeutic strategies for vascular complications in diabetes.</description><identifier>EISSN: 1879-1484</identifier><identifier>DOI: 10.1016/j.atherosclerosis.2012.10.062</identifier><identifier>PMID: 23177014</identifier><language>eng</language><publisher>Ireland</publisher><subject>Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - physiology ; Diabetes Mellitus, Experimental - enzymology ; Male ; Muscle, Smooth, Vascular - cytology ; Muscle, Smooth, Vascular - enzymology ; Nitric Oxide Synthase Type II - physiology ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Atherosclerosis, 2013-01, Vol.226 (1), p.88-94</ispartof><rights>Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23177014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Di Pietro, Natalia</creatorcontrib><creatorcontrib>Di Tomo, Pamela</creatorcontrib><creatorcontrib>Di Silvestre, Sara</creatorcontrib><creatorcontrib>Giardinelli, Annalisa</creatorcontrib><creatorcontrib>Pipino, Caterina</creatorcontrib><creatorcontrib>Morabito, Caterina</creatorcontrib><creatorcontrib>Formoso, Gloria</creatorcontrib><creatorcontrib>Mariggiò, Maria Addolorata</creatorcontrib><creatorcontrib>Pandolfi, Assunta</creatorcontrib><title>Increased iNOS activity in vascular smooth muscle cells from diabetic rats: potential role of Ca(2+)/calmodulin-dependent protein kinase II delta 2 (CaMKIIδ(2))</title><title>Atherosclerosis</title><addtitle>Atherosclerosis</addtitle><description>Inducible nitric oxide synthase (iNOS) expression may be increased by cytokine plasma levels contributing to vascular damage in diabetes. Besides transcriptional regulation, Ca(2+)/CaMKII may play a role in post-translationally controlled iNOS activity. We accordingly investigated the involvement of the Ca(2+)/CaMKIIδ(2) signaling pathway in regulating lipopolysaccharide (LPS)-induced iNOS activity in cultured aortic vascular smooth muscle cells (VSMCs) from diabetic rats.
VSMCs obtained from 10 diabetic rats (DR) and 10 control rats (CR) were stimulated with 20 μg/ml LPS. After 24 h, iNOS protein levels were 1.37 fold increased in DR- vs CR-VSMCs (p < 0.05; Western Blot), while iNOS activity (conversion l-((3)H)-arginine into l-((3)H)-citrulline) and intracellular nitrotyrosine levels (immunofluorescence) were about 2.7 fold greater in DR- than in CR-VSMCs. Interestingly, LPS increased intracellular Ca(2+) levels (Fluorescence video imaging) more markedly in DR- than in CR-VSMCs. This was associated with CaMKII activation by phosphorylation, a decreased amount of co-immunoprecipitating iNOS/CaMKIIδ(2) (Western Blot) and increased iNOS activity. The CaMKII inhibitor KN-93 abolished all the LPS-effects.
These results indicate that the Ca(2+)/CaMKIIδ(2) signaling pathway may be an important regulator of iNOS activity in diabetes, and hence contribute to the potential development of innovative therapeutic strategies for vascular complications in diabetes.</description><subject>Animals</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - physiology</subject><subject>Diabetes Mellitus, Experimental - enzymology</subject><subject>Male</subject><subject>Muscle, Smooth, Vascular - cytology</subject><subject>Muscle, Smooth, Vascular - enzymology</subject><subject>Nitric Oxide Synthase Type II - physiology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>1879-1484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kElOxDAQRS0kRDNdAdUGqVsoje2MzQ61GCKGXgDrlmNXhMGJg-0gcRzuwDk4E24Bm6pFPf1f_xNyzOicUVacvsxFeEZnvTSbqf2cU8bjbU4LvkV2WVUuEpZV2YTsef9CKc1KVu2QCU9ZWVKW7ZLPupcOhUcF-n71AEIG_a7DB-ge3oWXoxEOfGdteIZu3BiBRGM8tM52oLRoMGgJTgR_BoMN2ActDDgbQdvCUkz5yexUCtNZNRrdJwoH7FXEYHARjzavuo_-UNeg0AQBHKZLcXdT199fUz6bHZDtVhiPh397nzxdXjwur5Pb1VW9PL9NBsaLkLTICrnIi5wiUxjTNTEuzxZpKZsi5ZJy2eSxC2xLga3MWIUFKiWxyRdNxfJ0n0x_deNfbyP6sO6032QVPdrRrxkv06xIo3JEj_7QselQrQenO-E-1v-1pj9dkX7r</recordid><startdate>201301</startdate><enddate>201301</enddate><creator>Di Pietro, Natalia</creator><creator>Di Tomo, Pamela</creator><creator>Di Silvestre, Sara</creator><creator>Giardinelli, Annalisa</creator><creator>Pipino, Caterina</creator><creator>Morabito, Caterina</creator><creator>Formoso, Gloria</creator><creator>Mariggiò, Maria Addolorata</creator><creator>Pandolfi, Assunta</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201301</creationdate><title>Increased iNOS activity in vascular smooth muscle cells from diabetic rats: potential role of Ca(2+)/calmodulin-dependent protein kinase II delta 2 (CaMKIIδ(2))</title><author>Di Pietro, Natalia ; Di Tomo, Pamela ; Di Silvestre, Sara ; Giardinelli, Annalisa ; Pipino, Caterina ; Morabito, Caterina ; Formoso, Gloria ; Mariggiò, Maria Addolorata ; Pandolfi, Assunta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p126t-fe16c95650e1de770b00024937cb632c02cb5148ef7aefc418e6eddceb59b8153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 2 - physiology</topic><topic>Diabetes Mellitus, Experimental - enzymology</topic><topic>Male</topic><topic>Muscle, Smooth, Vascular - cytology</topic><topic>Muscle, Smooth, Vascular - enzymology</topic><topic>Nitric Oxide Synthase Type II - physiology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Di Pietro, Natalia</creatorcontrib><creatorcontrib>Di Tomo, Pamela</creatorcontrib><creatorcontrib>Di Silvestre, Sara</creatorcontrib><creatorcontrib>Giardinelli, Annalisa</creatorcontrib><creatorcontrib>Pipino, Caterina</creatorcontrib><creatorcontrib>Morabito, Caterina</creatorcontrib><creatorcontrib>Formoso, Gloria</creatorcontrib><creatorcontrib>Mariggiò, Maria Addolorata</creatorcontrib><creatorcontrib>Pandolfi, Assunta</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Atherosclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Di Pietro, Natalia</au><au>Di Tomo, Pamela</au><au>Di Silvestre, Sara</au><au>Giardinelli, Annalisa</au><au>Pipino, Caterina</au><au>Morabito, Caterina</au><au>Formoso, Gloria</au><au>Mariggiò, Maria Addolorata</au><au>Pandolfi, Assunta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased iNOS activity in vascular smooth muscle cells from diabetic rats: potential role of Ca(2+)/calmodulin-dependent protein kinase II delta 2 (CaMKIIδ(2))</atitle><jtitle>Atherosclerosis</jtitle><addtitle>Atherosclerosis</addtitle><date>2013-01</date><risdate>2013</risdate><volume>226</volume><issue>1</issue><spage>88</spage><epage>94</epage><pages>88-94</pages><eissn>1879-1484</eissn><abstract>Inducible nitric oxide synthase (iNOS) expression may be increased by cytokine plasma levels contributing to vascular damage in diabetes. Besides transcriptional regulation, Ca(2+)/CaMKII may play a role in post-translationally controlled iNOS activity. We accordingly investigated the involvement of the Ca(2+)/CaMKIIδ(2) signaling pathway in regulating lipopolysaccharide (LPS)-induced iNOS activity in cultured aortic vascular smooth muscle cells (VSMCs) from diabetic rats.
VSMCs obtained from 10 diabetic rats (DR) and 10 control rats (CR) were stimulated with 20 μg/ml LPS. After 24 h, iNOS protein levels were 1.37 fold increased in DR- vs CR-VSMCs (p < 0.05; Western Blot), while iNOS activity (conversion l-((3)H)-arginine into l-((3)H)-citrulline) and intracellular nitrotyrosine levels (immunofluorescence) were about 2.7 fold greater in DR- than in CR-VSMCs. Interestingly, LPS increased intracellular Ca(2+) levels (Fluorescence video imaging) more markedly in DR- than in CR-VSMCs. This was associated with CaMKII activation by phosphorylation, a decreased amount of co-immunoprecipitating iNOS/CaMKIIδ(2) (Western Blot) and increased iNOS activity. The CaMKII inhibitor KN-93 abolished all the LPS-effects.
These results indicate that the Ca(2+)/CaMKIIδ(2) signaling pathway may be an important regulator of iNOS activity in diabetes, and hence contribute to the potential development of innovative therapeutic strategies for vascular complications in diabetes.</abstract><cop>Ireland</cop><pmid>23177014</pmid><doi>10.1016/j.atherosclerosis.2012.10.062</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Calcium-Calmodulin-Dependent Protein Kinase Type 2 - physiology Diabetes Mellitus, Experimental - enzymology Male Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - enzymology Nitric Oxide Synthase Type II - physiology Rats Rats, Sprague-Dawley |
| title | Increased iNOS activity in vascular smooth muscle cells from diabetic rats: potential role of Ca(2+)/calmodulin-dependent protein kinase II delta 2 (CaMKIIδ(2)) |
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