Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest
Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts,...
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| Veröffentlicht in: | PloS one 2023-09, Vol.18 (9), p.e0291598 |
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| creator | Zhu, Xiangdong Li, Jing Wang, Huashan Gasior, Filip M Lee, Chunpei Lin, Shaoxia Justice, Cody N O'Donnell, J Michael Vanden Hoek, Terry L |
| description | Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 μM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest. |
| doi_str_mv | 10.1371/journal.pone.0291598 |
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Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 μM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0291598</identifier><identifier>PMID: 37713442</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine Triphosphate ; Animal models ; Animals ; Apoptosis ; Bioenergetics ; Biology and Life Sciences ; Cardiac arrest ; Cardiomyocytes ; Cerebral blood flow ; Disease Models, Animal ; Enzymes ; Glucose ; Glycolysis ; Heart ; Heart Arrest - drug therapy ; Ischemia ; Laboratory animals ; Lactic Acid ; Medicine and Health Sciences ; Metabolism ; Mice ; Modelling ; Muscle contraction ; Myocytes, Cardiac ; NAD ; Niacinamide - pharmacology ; Nicotinamide ; Physical Sciences ; Rats ; Recovery ; Reperfusion ; Research and Analysis Methods ; Rodentia ; Sorbitol ; Survival ; Ventilators</subject><ispartof>PloS one, 2023-09, Vol.18 (9), p.e0291598</ispartof><rights>Copyright: © 2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Zhu et al 2023 Zhu et al</rights><rights>2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 μM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.</description><subject>Adenosine Triphosphate</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Bioenergetics</subject><subject>Biology and Life Sciences</subject><subject>Cardiac arrest</subject><subject>Cardiomyocytes</subject><subject>Cerebral blood flow</subject><subject>Disease Models, Animal</subject><subject>Enzymes</subject><subject>Glucose</subject><subject>Glycolysis</subject><subject>Heart</subject><subject>Heart Arrest - drug therapy</subject><subject>Ischemia</subject><subject>Laboratory animals</subject><subject>Lactic Acid</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Modelling</subject><subject>Muscle contraction</subject><subject>Myocytes, Cardiac</subject><subject>NAD</subject><subject>Niacinamide - pharmacology</subject><subject>Nicotinamide</subject><subject>Physical Sciences</subject><subject>Rats</subject><subject>Recovery</subject><subject>Reperfusion</subject><subject>Research and Analysis Methods</subject><subject>Rodentia</subject><subject>Sorbitol</subject><subject>Survival</subject><subject>Ventilators</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUk1v1DAQjRCIloV_gMASFyS0iz8Sxz6hqnxVqsoFLlysiT0uXiXxYicr8e_xdtOqRRzsGXnePM88vap6yeiGiZa938Y5jdBvdnHEDeWaNVo9qk6ZFnwtORWP7-Un1bOct5Q2Qkn5tDoRbctEXfPT6udVsHEKIwzBIUmYp1guMoWcZyRXZx_fERgdCcMuxX0p5Dntwx56EkaSosNxIkMJfSbREwvJBbAE0oHoefXEQ5_xxRJX1Y_Pn76ff11ffvtycX52ubYNb6c14157a6WzCjgy7ZRusQzYOUBED-A4p9JT0ChRK0AuWNe4VnRa8XLEqnp95N31MZtFlmy4kg0vXFoWxMUR4SJszS6FAdIfEyGYm4eYrg2kKdgeDeO1twJ1o7Crra_BeWE72Vj0tbSKF64Py29zN6CzRYEE_QPSh5Ux_DLXcW8YbeiN7qvq7cKQ4u-5CGWGkC32PYwY5-PgraKa1QX65h_o_9erjyibYs4J_d00jJqDV267zMErZvFKaXt1f5O7pltziL9QcL9_</recordid><startdate>20230915</startdate><enddate>20230915</enddate><creator>Zhu, Xiangdong</creator><creator>Li, Jing</creator><creator>Wang, Huashan</creator><creator>Gasior, Filip M</creator><creator>Lee, Chunpei</creator><creator>Lin, Shaoxia</creator><creator>Justice, Cody N</creator><creator>O'Donnell, J Michael</creator><creator>Vanden Hoek, Terry L</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5627-8082</orcidid></search><sort><creationdate>20230915</creationdate><title>Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest</title><author>Zhu, Xiangdong ; Li, Jing ; Wang, Huashan ; Gasior, Filip M ; Lee, Chunpei ; Lin, Shaoxia ; Justice, Cody N ; O'Donnell, J Michael ; Vanden Hoek, Terry L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-12f9fcc6dc8a2e19d897e377bdaeeefaad2206f0a9e6e98ae231b5d73b982b983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adenosine Triphosphate</topic><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Bioenergetics</topic><topic>Biology and Life Sciences</topic><topic>Cardiac arrest</topic><topic>Cardiomyocytes</topic><topic>Cerebral blood flow</topic><topic>Disease Models, Animal</topic><topic>Enzymes</topic><topic>Glucose</topic><topic>Glycolysis</topic><topic>Heart</topic><topic>Heart Arrest - 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Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 μM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>37713442</pmid><doi>10.1371/journal.pone.0291598</doi><orcidid>https://orcid.org/0000-0002-5627-8082</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine Triphosphate Animal models Animals Apoptosis Bioenergetics Biology and Life Sciences Cardiac arrest Cardiomyocytes Cerebral blood flow Disease Models, Animal Enzymes Glucose Glycolysis Heart Heart Arrest - drug therapy Ischemia Laboratory animals Lactic Acid Medicine and Health Sciences Metabolism Mice Modelling Muscle contraction Myocytes, Cardiac NAD Niacinamide - pharmacology Nicotinamide Physical Sciences Rats Recovery Reperfusion Research and Analysis Methods Rodentia Sorbitol Survival Ventilators |
| title | Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest |
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