Hypercholesterolemia inhibits re-endothelialization of arterial injuries by TRPC channel activation

Objective After arterial injury, endothelial cell (EC) migration is essential for healing, but lipid oxidation products activate TRPC6 and TRPC5 ion channels, leading to increased intracellular calcium and inhibition of EC migration in vitro. The objective of this study was to further evaluate the r...

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Veröffentlicht in:Journal of vascular surgery 2015-10, Vol.62 (4), p.1040-1047.e2
Hauptverfasser: Rosenbaum, Michael A., MD, Chaudhuri, Pinaki, PhD, Graham, Linda M., MD
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container_end_page 1047.e2
container_issue 4
container_start_page 1040
container_title Journal of vascular surgery
container_volume 62
creator Rosenbaum, Michael A., MD
Chaudhuri, Pinaki, PhD
Graham, Linda M., MD
description Objective After arterial injury, endothelial cell (EC) migration is essential for healing, but lipid oxidation products activate TRPC6 and TRPC5 ion channels, leading to increased intracellular calcium and inhibition of EC migration in vitro. The objective of this study was to further evaluate the role of TRPC channels in EC migration in vitro and to validate in vitro findings in an in vivo model. Methods Mouse aortic ECs were cultured, and the effect of lysophosphatidylcholine, the major lysophospholipid in oxidized low-density lipoprotein, on migration was assessed in a razor-scrape assay. EC healing after a carotid injury with electrocautery was evaluated in wild-type (WT), TRPC6 −/− , and TRPC5 −/− mice receiving either a chow or high-cholesterol (HC) diet. Results Lysophosphatidylcholine inhibited EC migration of WT ECs to 22% of baseline and of TRPC5 −/− ECs to 53% of baseline but had minimal effect on TRPC6 −/− EC migration. Hypercholesterolemia severely impaired EC healing in vivo, with 51.4% ± 1.8% and 24.9% ± 2.0% of the injury resurfaced with ECs at 5 days in chow-fed and HC-fed WT mice, respectively ( P  < .001). Hypercholesterolemia did not impair healing in TRPC6 −/− mice, with coverage of 48.4% ± 3.4% and 46.8% ± 1.6% in chow-fed and HC-fed TRPC6 −/− mice, respectively. Hypercholesterolemia had a reduced inhibitory effect in TRPC5 −/− mice, with EC coverage of 51.7% ± 3.0% and 37.% ± 1.4% in chow-fed and HC-fed TRPC5 −/− mice, respectively. Conclusions Results suggest that activation of TRPC6 and TRPC5 channels is the key contributor to impaired endothelial healing of arterial injuries in hypercholesterolemic mice.
doi_str_mv 10.1016/j.jvs.2014.04.033
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The objective of this study was to further evaluate the role of TRPC channels in EC migration in vitro and to validate in vitro findings in an in vivo model. Methods Mouse aortic ECs were cultured, and the effect of lysophosphatidylcholine, the major lysophospholipid in oxidized low-density lipoprotein, on migration was assessed in a razor-scrape assay. EC healing after a carotid injury with electrocautery was evaluated in wild-type (WT), TRPC6 −/− , and TRPC5 −/− mice receiving either a chow or high-cholesterol (HC) diet. Results Lysophosphatidylcholine inhibited EC migration of WT ECs to 22% of baseline and of TRPC5 −/− ECs to 53% of baseline but had minimal effect on TRPC6 −/− EC migration. Hypercholesterolemia severely impaired EC healing in vivo, with 51.4% ± 1.8% and 24.9% ± 2.0% of the injury resurfaced with ECs at 5 days in chow-fed and HC-fed WT mice, respectively ( P  &lt; .001). Hypercholesterolemia did not impair healing in TRPC6 −/− mice, with coverage of 48.4% ± 3.4% and 46.8% ± 1.6% in chow-fed and HC-fed TRPC6 −/− mice, respectively. Hypercholesterolemia had a reduced inhibitory effect in TRPC5 −/− mice, with EC coverage of 51.7% ± 3.0% and 37.% ± 1.4% in chow-fed and HC-fed TRPC5 −/− mice, respectively. Conclusions Results suggest that activation of TRPC6 and TRPC5 channels is the key contributor to impaired endothelial healing of arterial injuries in hypercholesterolemic mice.</description><identifier>ISSN: 0741-5214</identifier><identifier>EISSN: 1097-6809</identifier><identifier>DOI: 10.1016/j.jvs.2014.04.033</identifier><identifier>PMID: 24820897</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Arteries - injuries ; Biomarkers - blood ; Calcium - analysis ; Cell Movement - physiology ; Endothelial Cells - physiology ; Endothelium, Vascular - physiology ; Hypercholesterolemia - blood ; Hypercholesterolemia - physiopathology ; Hypercholesterolemia - urine ; In Vitro Techniques ; Inflammation - blood ; Lysophosphatidylcholines - pharmacology ; Mice ; Oxidative Stress ; Surgery ; TRPC Cation Channels - physiology ; Wound Healing - physiology</subject><ispartof>Journal of vascular surgery, 2015-10, Vol.62 (4), p.1040-1047.e2</ispartof><rights>Society for Vascular Surgery</rights><rights>2015 Society for Vascular Surgery</rights><rights>Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. 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The objective of this study was to further evaluate the role of TRPC channels in EC migration in vitro and to validate in vitro findings in an in vivo model. Methods Mouse aortic ECs were cultured, and the effect of lysophosphatidylcholine, the major lysophospholipid in oxidized low-density lipoprotein, on migration was assessed in a razor-scrape assay. EC healing after a carotid injury with electrocautery was evaluated in wild-type (WT), TRPC6 −/− , and TRPC5 −/− mice receiving either a chow or high-cholesterol (HC) diet. Results Lysophosphatidylcholine inhibited EC migration of WT ECs to 22% of baseline and of TRPC5 −/− ECs to 53% of baseline but had minimal effect on TRPC6 −/− EC migration. Hypercholesterolemia severely impaired EC healing in vivo, with 51.4% ± 1.8% and 24.9% ± 2.0% of the injury resurfaced with ECs at 5 days in chow-fed and HC-fed WT mice, respectively ( P  &lt; .001). Hypercholesterolemia did not impair healing in TRPC6 −/− mice, with coverage of 48.4% ± 3.4% and 46.8% ± 1.6% in chow-fed and HC-fed TRPC6 −/− mice, respectively. Hypercholesterolemia had a reduced inhibitory effect in TRPC5 −/− mice, with EC coverage of 51.7% ± 3.0% and 37.% ± 1.4% in chow-fed and HC-fed TRPC5 −/− mice, respectively. Conclusions Results suggest that activation of TRPC6 and TRPC5 channels is the key contributor to impaired endothelial healing of arterial injuries in hypercholesterolemic mice.</description><subject>Animals</subject><subject>Arteries - injuries</subject><subject>Biomarkers - blood</subject><subject>Calcium - analysis</subject><subject>Cell Movement - physiology</subject><subject>Endothelial Cells - physiology</subject><subject>Endothelium, Vascular - physiology</subject><subject>Hypercholesterolemia - blood</subject><subject>Hypercholesterolemia - physiopathology</subject><subject>Hypercholesterolemia - urine</subject><subject>In Vitro Techniques</subject><subject>Inflammation - blood</subject><subject>Lysophosphatidylcholines - pharmacology</subject><subject>Mice</subject><subject>Oxidative Stress</subject><subject>Surgery</subject><subject>TRPC Cation Channels - physiology</subject><subject>Wound Healing - physiology</subject><issn>0741-5214</issn><issn>1097-6809</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU-LFDEQxYMo7rj6AbxIH730WPnTnW4EQQZ1hQWX3fUcknQ1kzaTjEn3wPjpN-OsHjwIBQXFrx71XhHymsKaAm3fTevpkNcMqFhDKc6fkBWFXtZtB_1TsgIpaN0wKi7Ii5wnAEqbTj4nF0x0DLperoi9Ou4x2W30mGdMpe2crlzYOuPmXCWsMQxx3qJ32rtfenYxVHGsdCp0GRV0WpLDXJljdX97s6nsVoeAvtJ2doff_EvybNQ-46vHfkm-f_50v7mqr799-br5eF3bctVcc1MuGmHklkqUHTRmaIXpKQPTWxiE6RrL2sH2o21HwznTjWwZckltD9AhvyRvz7r7FH8uxY_auWzRex0wLllRSaXoRM_bgtIzalPMOeGo9sntdDoqCuqUrZpUyVadslVQivOy8-ZRfjE7HP5u_AmzAO_PABaTB4dJZeswWBxcQjurIbr_yn_4Z9t6F5zV_gceMU9xSaGkp6jKTIG6Oz339FsqinleXD0AVHegVA</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Rosenbaum, Michael A., MD</creator><creator>Chaudhuri, Pinaki, PhD</creator><creator>Graham, Linda M., MD</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope></search><sort><creationdate>20151001</creationdate><title>Hypercholesterolemia inhibits re-endothelialization of arterial injuries by TRPC channel activation</title><author>Rosenbaum, Michael A., MD ; Chaudhuri, Pinaki, PhD ; Graham, Linda M., MD</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c587t-3b897f0f3c17e7805bd64b9120b9c0d4b85c26dc9fc6fb332a5762e371c9008e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Arteries - injuries</topic><topic>Biomarkers - blood</topic><topic>Calcium - analysis</topic><topic>Cell Movement - physiology</topic><topic>Endothelial Cells - physiology</topic><topic>Endothelium, Vascular - physiology</topic><topic>Hypercholesterolemia - blood</topic><topic>Hypercholesterolemia - physiopathology</topic><topic>Hypercholesterolemia - urine</topic><topic>In Vitro Techniques</topic><topic>Inflammation - blood</topic><topic>Lysophosphatidylcholines - pharmacology</topic><topic>Mice</topic><topic>Oxidative Stress</topic><topic>Surgery</topic><topic>TRPC Cation Channels - physiology</topic><topic>Wound Healing - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rosenbaum, Michael A., MD</creatorcontrib><creatorcontrib>Chaudhuri, Pinaki, PhD</creatorcontrib><creatorcontrib>Graham, Linda M., MD</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>Journal of vascular surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rosenbaum, Michael A., MD</au><au>Chaudhuri, Pinaki, PhD</au><au>Graham, Linda M., MD</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypercholesterolemia inhibits re-endothelialization of arterial injuries by TRPC channel activation</atitle><jtitle>Journal of vascular surgery</jtitle><addtitle>J Vasc Surg</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>62</volume><issue>4</issue><spage>1040</spage><epage>1047.e2</epage><pages>1040-1047.e2</pages><issn>0741-5214</issn><eissn>1097-6809</eissn><abstract>Objective After arterial injury, endothelial cell (EC) migration is essential for healing, but lipid oxidation products activate TRPC6 and TRPC5 ion channels, leading to increased intracellular calcium and inhibition of EC migration in vitro. The objective of this study was to further evaluate the role of TRPC channels in EC migration in vitro and to validate in vitro findings in an in vivo model. Methods Mouse aortic ECs were cultured, and the effect of lysophosphatidylcholine, the major lysophospholipid in oxidized low-density lipoprotein, on migration was assessed in a razor-scrape assay. EC healing after a carotid injury with electrocautery was evaluated in wild-type (WT), TRPC6 −/− , and TRPC5 −/− mice receiving either a chow or high-cholesterol (HC) diet. Results Lysophosphatidylcholine inhibited EC migration of WT ECs to 22% of baseline and of TRPC5 −/− ECs to 53% of baseline but had minimal effect on TRPC6 −/− EC migration. Hypercholesterolemia severely impaired EC healing in vivo, with 51.4% ± 1.8% and 24.9% ± 2.0% of the injury resurfaced with ECs at 5 days in chow-fed and HC-fed WT mice, respectively ( P  &lt; .001). Hypercholesterolemia did not impair healing in TRPC6 −/− mice, with coverage of 48.4% ± 3.4% and 46.8% ± 1.6% in chow-fed and HC-fed TRPC6 −/− mice, respectively. Hypercholesterolemia had a reduced inhibitory effect in TRPC5 −/− mice, with EC coverage of 51.7% ± 3.0% and 37.% ± 1.4% in chow-fed and HC-fed TRPC5 −/− mice, respectively. Conclusions Results suggest that activation of TRPC6 and TRPC5 channels is the key contributor to impaired endothelial healing of arterial injuries in hypercholesterolemic mice.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24820897</pmid><doi>10.1016/j.jvs.2014.04.033</doi><oa>free_for_read</oa></addata></record>
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subjects Animals
Arteries - injuries
Biomarkers - blood
Calcium - analysis
Cell Movement - physiology
Endothelial Cells - physiology
Endothelium, Vascular - physiology
Hypercholesterolemia - blood
Hypercholesterolemia - physiopathology
Hypercholesterolemia - urine
In Vitro Techniques
Inflammation - blood
Lysophosphatidylcholines - pharmacology
Mice
Oxidative Stress
Surgery
TRPC Cation Channels - physiology
Wound Healing - physiology
title Hypercholesterolemia inhibits re-endothelialization of arterial injuries by TRPC channel activation
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