Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis
Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atheros...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2014-12, Vol.63 (12), p.4275-4290 |
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| creator | Fang, Pu Zhang, Daqing Cheng, Zhongjian Yan, Chenghui Jiang, Xiaohua Kruger, Warren D Meng, Shu Arning, Erland Bottiglieri, Teodoro Choi, Eric T Han, Yaling Yang, Xiao-Feng Wang, Hong |
| description | Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine β-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE(-/-)) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine-to-s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation. |
| doi_str_mv | 10.2337/db14-0809 |
| format | Article |
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However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine β-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE(-/-)) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine-to-s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db14-0809</identifier><identifier>PMID: 25008174</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Animals ; Apolipoproteins E - genetics ; Atherosclerosis ; Atherosclerosis - complications ; Atherosclerosis - immunology ; Cardiovascular disease ; Cell Differentiation - immunology ; Complications ; Correlation analysis ; Cystathionine beta-Synthase - genetics ; Deoxyribonucleic acid ; Diet, High-Fat - adverse effects ; Disease Models, Animal ; DNA ; Humans ; Hyperglycemia - complications ; Hyperglycemia - immunology ; Hyperhomocysteinemia - complications ; Hyperhomocysteinemia - immunology ; Inflammation - immunology ; Macrophages - immunology ; Mice ; Mice, Transgenic ; Monocytes - immunology ; Rodents</subject><ispartof>Diabetes (New York, N.Y.), 2014-12, Vol.63 (12), p.4275-4290</ispartof><rights>2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.</rights><rights>Copyright American Diabetes Association Dec 2014</rights><rights>2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c502t-72b0d459adb1aab184b751520abb35375fd5e290543595b16c790df9c1fe5db13</citedby><cites>FETCH-LOGICAL-c502t-72b0d459adb1aab184b751520abb35375fd5e290543595b16c790df9c1fe5db13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237991/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237991/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25008174$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fang, Pu</creatorcontrib><creatorcontrib>Zhang, Daqing</creatorcontrib><creatorcontrib>Cheng, Zhongjian</creatorcontrib><creatorcontrib>Yan, Chenghui</creatorcontrib><creatorcontrib>Jiang, Xiaohua</creatorcontrib><creatorcontrib>Kruger, Warren D</creatorcontrib><creatorcontrib>Meng, Shu</creatorcontrib><creatorcontrib>Arning, Erland</creatorcontrib><creatorcontrib>Bottiglieri, Teodoro</creatorcontrib><creatorcontrib>Choi, Eric T</creatorcontrib><creatorcontrib>Han, Yaling</creatorcontrib><creatorcontrib>Yang, Xiao-Feng</creatorcontrib><creatorcontrib>Wang, Hong</creatorcontrib><title>Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine β-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE(-/-)) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine-to-s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation.</description><subject>Animals</subject><subject>Apolipoproteins E - genetics</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - complications</subject><subject>Atherosclerosis - immunology</subject><subject>Cardiovascular disease</subject><subject>Cell Differentiation - immunology</subject><subject>Complications</subject><subject>Correlation analysis</subject><subject>Cystathionine beta-Synthase - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>Diet, High-Fat - adverse effects</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>Humans</subject><subject>Hyperglycemia - complications</subject><subject>Hyperglycemia - immunology</subject><subject>Hyperhomocysteinemia - complications</subject><subject>Hyperhomocysteinemia - immunology</subject><subject>Inflammation - immunology</subject><subject>Macrophages - immunology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Monocytes - immunology</subject><subject>Rodents</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9rFTEUxYMo9rW68AvIgBtdTHvz72WyEaSoLRTcVHAXMkmmL2UmGZNMYb69GV4t6kYCyeL-zsm99yD0BsM5oVRc2B6zFjqQz9AOSypbSsSP52gHgEmLhRQn6DTnewDY1_MSnRAO0GHBdmi-WmeXDnGKZs3F-eAmr5s5FheK18Xl5rABd-Nqtkrrg12Ms40Pw6inSZeY1maKocqLa6wfBpeOUh9Do4NtdDm4FLMZt9vnV-jFoMfsXj--Z-j7l8-3l1ftzbev15efblrDgZRWkB4s41LX2bTuccd6wTEnoPuecir4YLkjEjijXPIe742QYAdp8OB41dAz9PHoOy_95KypTSU9qjn5SadVRe3V35XgD-ouPihGqJByM3j_aJDiz8XloiafjRtHHVxcssIdJYRxhun_0T0RIKjsuoq--we9j0sKdROVqh-LGher1IcjZerOcnLDU98Y1Ba52iJXW-SVffvnoE_k74zpL1RGqos</recordid><startdate>20141201</startdate><enddate>20141201</enddate><creator>Fang, Pu</creator><creator>Zhang, Daqing</creator><creator>Cheng, Zhongjian</creator><creator>Yan, Chenghui</creator><creator>Jiang, Xiaohua</creator><creator>Kruger, Warren D</creator><creator>Meng, Shu</creator><creator>Arning, Erland</creator><creator>Bottiglieri, Teodoro</creator><creator>Choi, Eric T</creator><creator>Han, Yaling</creator><creator>Yang, Xiao-Feng</creator><creator>Wang, Hong</creator><general>American Diabetes Association</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>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20141201</creationdate><title>Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis</title><author>Fang, Pu ; Zhang, Daqing ; Cheng, Zhongjian ; Yan, Chenghui ; Jiang, Xiaohua ; Kruger, Warren D ; Meng, Shu ; Arning, Erland ; Bottiglieri, Teodoro ; Choi, Eric T ; Han, Yaling ; Yang, Xiao-Feng ; Wang, Hong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c502t-72b0d459adb1aab184b751520abb35375fd5e290543595b16c790df9c1fe5db13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Apolipoproteins E - genetics</topic><topic>Atherosclerosis</topic><topic>Atherosclerosis - complications</topic><topic>Atherosclerosis - immunology</topic><topic>Cardiovascular disease</topic><topic>Cell Differentiation - immunology</topic><topic>Complications</topic><topic>Correlation analysis</topic><topic>Cystathionine beta-Synthase - genetics</topic><topic>Deoxyribonucleic acid</topic><topic>Diet, High-Fat - adverse effects</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>Humans</topic><topic>Hyperglycemia - complications</topic><topic>Hyperglycemia - immunology</topic><topic>Hyperhomocysteinemia - complications</topic><topic>Hyperhomocysteinemia - immunology</topic><topic>Inflammation - immunology</topic><topic>Macrophages - immunology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Monocytes - immunology</topic><topic>Rodents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fang, Pu</creatorcontrib><creatorcontrib>Zhang, Daqing</creatorcontrib><creatorcontrib>Cheng, Zhongjian</creatorcontrib><creatorcontrib>Yan, Chenghui</creatorcontrib><creatorcontrib>Jiang, Xiaohua</creatorcontrib><creatorcontrib>Kruger, Warren D</creatorcontrib><creatorcontrib>Meng, Shu</creatorcontrib><creatorcontrib>Arning, Erland</creatorcontrib><creatorcontrib>Bottiglieri, Teodoro</creatorcontrib><creatorcontrib>Choi, Eric T</creatorcontrib><creatorcontrib>Han, Yaling</creatorcontrib><creatorcontrib>Yang, Xiao-Feng</creatorcontrib><creatorcontrib>Wang, Hong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fang, Pu</au><au>Zhang, Daqing</au><au>Cheng, Zhongjian</au><au>Yan, Chenghui</au><au>Jiang, Xiaohua</au><au>Kruger, Warren D</au><au>Meng, Shu</au><au>Arning, Erland</au><au>Bottiglieri, Teodoro</au><au>Choi, Eric T</au><au>Han, Yaling</au><au>Yang, Xiao-Feng</au><au>Wang, Hong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2014-12-01</date><risdate>2014</risdate><volume>63</volume><issue>12</issue><spage>4275</spage><epage>4290</epage><pages>4275-4290</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Hyperhomocysteinemia (HHcy) is associated with increased diabetic cardiovascular diseases. However, the role of HHcy in atherogenesis associated with hyperglycemia (HG) remains unknown. To examine the role and mechanisms by which HHcy accelerates HG-induced atherosclerosis, we established an atherosclerosis-susceptible HHcy and HG mouse model. HHcy was established in mice deficient in cystathionine β-synthase (Cbs) in which the homocysteine (Hcy) level could be lowered by inducing transgenic human CBS (Tg-hCBS) using Zn supplementation. HG was induced by streptozotocin injection. Atherosclerosis was induced by crossing Tg-hCBS Cbs mice with apolipoprotein E-deficient (ApoE(-/-)) mice and feeding them a high-fat diet for 2 weeks. We demonstrated that HHcy and HG accelerated atherosclerosis and increased lesion monocytes (MCs) and macrophages (MØs) and further increased inflammatory MC and MØ levels in peripheral tissues. Furthermore, Hcy-lowering reversed circulating mononuclear cells, MC, and inflammatory MC and MC-derived MØ levels. In addition, inflammatory MC correlated positively with plasma Hcy levels and negatively with plasma s-adenosylmethionine-to-s-adenosylhomocysteine ratios. Finally, l-Hcy and d-glucose promoted inflammatory MC differentiation in primary mouse splenocytes, which was reversed by adenoviral DNA methyltransferase-1. HHcy and HG, individually and synergistically, accelerated atherosclerosis and inflammatory MC and MØ differentiation, at least in part, via DNA hypomethylation.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>25008174</pmid><doi>10.2337/db14-0809</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apolipoproteins E - genetics Atherosclerosis Atherosclerosis - complications Atherosclerosis - immunology Cardiovascular disease Cell Differentiation - immunology Complications Correlation analysis Cystathionine beta-Synthase - genetics Deoxyribonucleic acid Diet, High-Fat - adverse effects Disease Models, Animal DNA Humans Hyperglycemia - complications Hyperglycemia - immunology Hyperhomocysteinemia - complications Hyperhomocysteinemia - immunology Inflammation - immunology Macrophages - immunology Mice Mice, Transgenic Monocytes - immunology Rodents |
| title | Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis |
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