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Donor pretreatment with adenosine monophosphate-activated protein kinase activator protects cardiac grafts from cold ischaemia/reperfusion injury

OBJECTIVES Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy metabolism and has been shown to be protective in ischaemia/reperfusion injury (IRI). We hypothesized that preactivation of AMPK with an activator before donor heart procurement could protect heart gra...

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Published in:European journal of cardio-thoracic surgery 2016-05, Vol.49 (5), p.1354-1360
Main Authors: Yang, Chao, Xu, Honglai, Cai, Lanjun, Du, Xiaoxiao, Jiang, Yinan, Zhang, Yong, Zhou, Hongmin, Chen, Zhonghua Klaus
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container_title European journal of cardio-thoracic surgery
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creator Yang, Chao
Xu, Honglai
Cai, Lanjun
Du, Xiaoxiao
Jiang, Yinan
Zhang, Yong
Zhou, Hongmin
Chen, Zhonghua Klaus
description OBJECTIVES Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy metabolism and has been shown to be protective in ischaemia/reperfusion injury (IRI). We hypothesized that preactivation of AMPK with an activator before donor heart procurement could protect heart grafts from cold IRI. METHODS Donor Sprague–Dawley rats were injected intravenously with AMPK activator 5-amino-imidazole-4-carboxamide ribonucleotide (AICAR) or vehicle 30 min before heart procurement. Heart grafts were then preserved in histidine–tryptophan–ketoglutarate (HTK) solution at 4°C for 8 h. After preservation, grafts were immediately mounted on the Langendorff perfusion system and perfused with Krebs–Henseleit buffer at 37°C for 1 h. Adenosine triphosphate (ATP) and malondialdehyde (MDA) content in graft tissue were quantified post-preservation and post-reperfusion. After reperfusion, isolated heart function was assessed using a pressure transducer; cumulative release of creatine kinase (CK) and lactate dehydrogenase (LDH) into the perfusate was measured to assess cardiomyocyte necrosis; ultrastructural changes in the mitochondria of the grafts were examined using transmission electron microscopy (TEM). RESULTS After preservation, myocardial ATP content in the pretreated hearts was significantly higher than in the control hearts (3.247 ± 0.3034 vs 1.817 ± 0.2533 µmol/g protein; P < 0.05). AICAR-pretreated heart grafts exhibited significantly higher coronary flow (9.667 ± 0.3159 vs 8.033 ± 0.2459 ml/min; P < 0.05) and left ventricular developing pressure (58.67 ± 2.894 vs 42.67 ± 3.333 mmHg; P < 0.05) than the vehicle treated after reperfusion. Cumulative release of CK (300.0 ± 25.30 vs 431.7 ± 42.39 U/l; P < 0.05) and LDH (228.0 ± 16.68 vs 366.8 ± 57.41 U/l; P < 0.05) in the perfusate was significantly lower in the AICAR-pretreated group than that in the control group. Myocardial MDA content was also reduced in the pretreated group (0.5167 ± 0.1046 vs 0.9333 ± 0.1333 nmol/mg protein; P < 0.05). TEM suggested that the mitochondrial structure of AICAR-pretreated hearts was much better preserved. Moreover, AICAR-pretreated hearts significantly diminished cytosolic cytochrome c release after reperfusion. CONCLUSIONS This study demonstrates that pretreatment with AMPK activator AICAR significantly protects heart grafts from extended cold IRI. This novel protocol may be useful and feasible in clinical heart transplantation.
doi_str_mv 10.1093/ejcts/ezv413
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We hypothesized that preactivation of AMPK with an activator before donor heart procurement could protect heart grafts from cold IRI. METHODS Donor Sprague–Dawley rats were injected intravenously with AMPK activator 5-amino-imidazole-4-carboxamide ribonucleotide (AICAR) or vehicle 30 min before heart procurement. Heart grafts were then preserved in histidine–tryptophan–ketoglutarate (HTK) solution at 4°C for 8 h. After preservation, grafts were immediately mounted on the Langendorff perfusion system and perfused with Krebs–Henseleit buffer at 37°C for 1 h. Adenosine triphosphate (ATP) and malondialdehyde (MDA) content in graft tissue were quantified post-preservation and post-reperfusion. After reperfusion, isolated heart function was assessed using a pressure transducer; cumulative release of creatine kinase (CK) and lactate dehydrogenase (LDH) into the perfusate was measured to assess cardiomyocyte necrosis; ultrastructural changes in the mitochondria of the grafts were examined using transmission electron microscopy (TEM). RESULTS After preservation, myocardial ATP content in the pretreated hearts was significantly higher than in the control hearts (3.247 ± 0.3034 vs 1.817 ± 0.2533 µmol/g protein; P < 0.05). AICAR-pretreated heart grafts exhibited significantly higher coronary flow (9.667 ± 0.3159 vs 8.033 ± 0.2459 ml/min; P < 0.05) and left ventricular developing pressure (58.67 ± 2.894 vs 42.67 ± 3.333 mmHg; P < 0.05) than the vehicle treated after reperfusion. Cumulative release of CK (300.0 ± 25.30 vs 431.7 ± 42.39 U/l; P < 0.05) and LDH (228.0 ± 16.68 vs 366.8 ± 57.41 U/l; P < 0.05) in the perfusate was significantly lower in the AICAR-pretreated group than that in the control group. Myocardial MDA content was also reduced in the pretreated group (0.5167 ± 0.1046 vs 0.9333 ± 0.1333 nmol/mg protein; P < 0.05). TEM suggested that the mitochondrial structure of AICAR-pretreated hearts was much better preserved. Moreover, AICAR-pretreated hearts significantly diminished cytosolic cytochrome c release after reperfusion. CONCLUSIONS This study demonstrates that pretreatment with AMPK activator AICAR significantly protects heart grafts from extended cold IRI. This novel protocol may be useful and feasible in clinical heart transplantation.]]></description><identifier>ISSN: 1010-7940</identifier><identifier>EISSN: 1873-734X</identifier><identifier>DOI: 10.1093/ejcts/ezv413</identifier><identifier>PMID: 26609046</identifier><language>eng</language><publisher>Germany: Oxford University Press</publisher><subject>Adenosine Monophosphate - therapeutic use ; Animals ; Heart - physiology ; Heart Transplantation ; Hypothermia, Induced - methods ; Male ; Organ Preservation Solutions - therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury - prevention &amp; control ; Tissue Donors ; Tissue Preservation ; Transplants</subject><ispartof>European journal of cardio-thoracic surgery, 2016-05, Vol.49 (5), p.1354-1360</ispartof><rights>The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. 2015</rights><rights>The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c361t-38196cec5389a8804248947e61123557f8415ec15eed3e86b50edd3b2b2022893</citedby><cites>FETCH-LOGICAL-c361t-38196cec5389a8804248947e61123557f8415ec15eed3e86b50edd3b2b2022893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26609046$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Chao</creatorcontrib><creatorcontrib>Xu, Honglai</creatorcontrib><creatorcontrib>Cai, Lanjun</creatorcontrib><creatorcontrib>Du, Xiaoxiao</creatorcontrib><creatorcontrib>Jiang, Yinan</creatorcontrib><creatorcontrib>Zhang, Yong</creatorcontrib><creatorcontrib>Zhou, Hongmin</creatorcontrib><creatorcontrib>Chen, Zhonghua Klaus</creatorcontrib><title>Donor pretreatment with adenosine monophosphate-activated protein kinase activator protects cardiac grafts from cold ischaemia/reperfusion injury</title><title>European journal of cardio-thoracic surgery</title><addtitle>Eur J Cardiothorac Surg</addtitle><description><![CDATA[OBJECTIVES Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy metabolism and has been shown to be protective in ischaemia/reperfusion injury (IRI). We hypothesized that preactivation of AMPK with an activator before donor heart procurement could protect heart grafts from cold IRI. METHODS Donor Sprague–Dawley rats were injected intravenously with AMPK activator 5-amino-imidazole-4-carboxamide ribonucleotide (AICAR) or vehicle 30 min before heart procurement. Heart grafts were then preserved in histidine–tryptophan–ketoglutarate (HTK) solution at 4°C for 8 h. After preservation, grafts were immediately mounted on the Langendorff perfusion system and perfused with Krebs–Henseleit buffer at 37°C for 1 h. Adenosine triphosphate (ATP) and malondialdehyde (MDA) content in graft tissue were quantified post-preservation and post-reperfusion. After reperfusion, isolated heart function was assessed using a pressure transducer; cumulative release of creatine kinase (CK) and lactate dehydrogenase (LDH) into the perfusate was measured to assess cardiomyocyte necrosis; ultrastructural changes in the mitochondria of the grafts were examined using transmission electron microscopy (TEM). RESULTS After preservation, myocardial ATP content in the pretreated hearts was significantly higher than in the control hearts (3.247 ± 0.3034 vs 1.817 ± 0.2533 µmol/g protein; P < 0.05). AICAR-pretreated heart grafts exhibited significantly higher coronary flow (9.667 ± 0.3159 vs 8.033 ± 0.2459 ml/min; P < 0.05) and left ventricular developing pressure (58.67 ± 2.894 vs 42.67 ± 3.333 mmHg; P < 0.05) than the vehicle treated after reperfusion. Cumulative release of CK (300.0 ± 25.30 vs 431.7 ± 42.39 U/l; P < 0.05) and LDH (228.0 ± 16.68 vs 366.8 ± 57.41 U/l; P < 0.05) in the perfusate was significantly lower in the AICAR-pretreated group than that in the control group. Myocardial MDA content was also reduced in the pretreated group (0.5167 ± 0.1046 vs 0.9333 ± 0.1333 nmol/mg protein; P < 0.05). TEM suggested that the mitochondrial structure of AICAR-pretreated hearts was much better preserved. Moreover, AICAR-pretreated hearts significantly diminished cytosolic cytochrome c release after reperfusion. CONCLUSIONS This study demonstrates that pretreatment with AMPK activator AICAR significantly protects heart grafts from extended cold IRI. This novel protocol may be useful and feasible in clinical heart transplantation.]]></description><subject>Adenosine Monophosphate - therapeutic use</subject><subject>Animals</subject><subject>Heart - physiology</subject><subject>Heart Transplantation</subject><subject>Hypothermia, Induced - methods</subject><subject>Male</subject><subject>Organ Preservation Solutions - therapeutic use</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reperfusion Injury - prevention &amp; control</subject><subject>Tissue Donors</subject><subject>Tissue Preservation</subject><subject>Transplants</subject><issn>1010-7940</issn><issn>1873-734X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp9kctOwzAQRS0E4r1jjbyDBaF-JI6zROUpIbEBiV3kOhPq0tjBdkDlL_hjXFpYshh5RnPm6soXoSNKzimp-AhmOoYRfL7nlG-gXSpLnpU8f95MPaEkK6uc7KC9EGaEEMFZuY12mBCkIrnYRV-XzjqPew_Rg4od2Ig_TJxi1YB1wVjAXSL6qQv9VEXIlI7mPTVNunERjMWvxqoAeL34EUuLZApr5RujNH7xqk1j612HtZs32AQ9VdAZNfLQg2-HYJzFxs4GvzhAW62aBzhcv_vo6frqcXyb3T_c3I0v7jPNBY0Zl7QSGnTBZaWkJDnLZZWXIChlvCjKVua0AJ0KGg5STAoCTcMnbMIIY7Li--h0pZvsvg0QYt0lWzCfKwtuCDUtZVEWrBJL9GyFau9C8NDWvTed8ouaknoZQv0TQr0KIeHHa-Vh0kHzB__-egJOVoAb-v-lvgHHrJYP</recordid><startdate>201605</startdate><enddate>201605</enddate><creator>Yang, Chao</creator><creator>Xu, Honglai</creator><creator>Cai, Lanjun</creator><creator>Du, Xiaoxiao</creator><creator>Jiang, Yinan</creator><creator>Zhang, Yong</creator><creator>Zhou, Hongmin</creator><creator>Chen, Zhonghua Klaus</creator><general>Oxford University Press</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>7X8</scope></search><sort><creationdate>201605</creationdate><title>Donor pretreatment with adenosine monophosphate-activated protein kinase activator protects cardiac grafts from cold ischaemia/reperfusion injury</title><author>Yang, Chao ; Xu, Honglai ; Cai, Lanjun ; Du, Xiaoxiao ; Jiang, Yinan ; Zhang, Yong ; Zhou, Hongmin ; Chen, Zhonghua Klaus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c361t-38196cec5389a8804248947e61123557f8415ec15eed3e86b50edd3b2b2022893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adenosine Monophosphate - therapeutic use</topic><topic>Animals</topic><topic>Heart - physiology</topic><topic>Heart Transplantation</topic><topic>Hypothermia, Induced - methods</topic><topic>Male</topic><topic>Organ Preservation Solutions - therapeutic use</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reperfusion Injury - prevention &amp; control</topic><topic>Tissue Donors</topic><topic>Tissue Preservation</topic><topic>Transplants</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yang, Chao</creatorcontrib><creatorcontrib>Xu, Honglai</creatorcontrib><creatorcontrib>Cai, Lanjun</creatorcontrib><creatorcontrib>Du, Xiaoxiao</creatorcontrib><creatorcontrib>Jiang, Yinan</creatorcontrib><creatorcontrib>Zhang, Yong</creatorcontrib><creatorcontrib>Zhou, Hongmin</creatorcontrib><creatorcontrib>Chen, Zhonghua Klaus</creatorcontrib><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>European journal of cardio-thoracic surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Chao</au><au>Xu, Honglai</au><au>Cai, Lanjun</au><au>Du, Xiaoxiao</au><au>Jiang, Yinan</au><au>Zhang, Yong</au><au>Zhou, Hongmin</au><au>Chen, Zhonghua Klaus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Donor pretreatment with adenosine monophosphate-activated protein kinase activator protects cardiac grafts from cold ischaemia/reperfusion injury</atitle><jtitle>European journal of cardio-thoracic surgery</jtitle><addtitle>Eur J Cardiothorac Surg</addtitle><date>2016-05</date><risdate>2016</risdate><volume>49</volume><issue>5</issue><spage>1354</spage><epage>1360</epage><pages>1354-1360</pages><issn>1010-7940</issn><eissn>1873-734X</eissn><abstract><![CDATA[OBJECTIVES Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy metabolism and has been shown to be protective in ischaemia/reperfusion injury (IRI). We hypothesized that preactivation of AMPK with an activator before donor heart procurement could protect heart grafts from cold IRI. METHODS Donor Sprague–Dawley rats were injected intravenously with AMPK activator 5-amino-imidazole-4-carboxamide ribonucleotide (AICAR) or vehicle 30 min before heart procurement. Heart grafts were then preserved in histidine–tryptophan–ketoglutarate (HTK) solution at 4°C for 8 h. After preservation, grafts were immediately mounted on the Langendorff perfusion system and perfused with Krebs–Henseleit buffer at 37°C for 1 h. Adenosine triphosphate (ATP) and malondialdehyde (MDA) content in graft tissue were quantified post-preservation and post-reperfusion. After reperfusion, isolated heart function was assessed using a pressure transducer; cumulative release of creatine kinase (CK) and lactate dehydrogenase (LDH) into the perfusate was measured to assess cardiomyocyte necrosis; ultrastructural changes in the mitochondria of the grafts were examined using transmission electron microscopy (TEM). RESULTS After preservation, myocardial ATP content in the pretreated hearts was significantly higher than in the control hearts (3.247 ± 0.3034 vs 1.817 ± 0.2533 µmol/g protein; P < 0.05). AICAR-pretreated heart grafts exhibited significantly higher coronary flow (9.667 ± 0.3159 vs 8.033 ± 0.2459 ml/min; P < 0.05) and left ventricular developing pressure (58.67 ± 2.894 vs 42.67 ± 3.333 mmHg; P < 0.05) than the vehicle treated after reperfusion. Cumulative release of CK (300.0 ± 25.30 vs 431.7 ± 42.39 U/l; P < 0.05) and LDH (228.0 ± 16.68 vs 366.8 ± 57.41 U/l; P < 0.05) in the perfusate was significantly lower in the AICAR-pretreated group than that in the control group. Myocardial MDA content was also reduced in the pretreated group (0.5167 ± 0.1046 vs 0.9333 ± 0.1333 nmol/mg protein; P < 0.05). TEM suggested that the mitochondrial structure of AICAR-pretreated hearts was much better preserved. Moreover, AICAR-pretreated hearts significantly diminished cytosolic cytochrome c release after reperfusion. CONCLUSIONS This study demonstrates that pretreatment with AMPK activator AICAR significantly protects heart grafts from extended cold IRI. This novel protocol may be useful and feasible in clinical heart transplantation.]]></abstract><cop>Germany</cop><pub>Oxford University Press</pub><pmid>26609046</pmid><doi>10.1093/ejcts/ezv413</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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subjects Adenosine Monophosphate - therapeutic use
Animals
Heart - physiology
Heart Transplantation
Hypothermia, Induced - methods
Male
Organ Preservation Solutions - therapeutic use
Rats
Rats, Sprague-Dawley
Reperfusion Injury - prevention & control
Tissue Donors
Tissue Preservation
Transplants
title Donor pretreatment with adenosine monophosphate-activated protein kinase activator protects cardiac grafts from cold ischaemia/reperfusion injury
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