Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis
Identifieur interne : 000D90 ( Main/Exploration ); précédent : 000D89; suivant : 000D91Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis
Auteurs : Santosh Karnewar [Inde] ; Sathish Babu Vasamsetti [Inde] ; Raja Gopoju [Inde] ; Anantha Koteswararao Kanugula [Inde] ; Sai Krishna Ganji [Inde] ; Sripadi Prabhakar [Inde] ; Nandini Rangaraj [Inde] ; Nitin Tupperwar [Inde] ; Jerald Mahesh Kumar [Inde] ; Srigiridhar Kotamraju [Inde]Source :
- Scientific Reports [ 2045-2322 ] ; 2016.
Abstract
Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE−/− mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3 treatment not only completely reversed Mito-Esc-mediated mitochondrial biogenetic marker expressions but also caused endothelial cell death. Furthermore, Mito-Esc administration to ApoE−/− mice greatly alleviated Ang-II-induced atheromatous plaque formation, monocyte infiltration and serum pro-inflammatory cytokines levels. We conclude that Mito-Esc is preferentially taken up by the mitochondria and preserves endothelial cell survival during oxidative stress by modulating NO generation via AMPK. Also, Mito-Esc-induced SIRT3 plays a pivotal role in mediating mitochondrial biogenesis and perhaps contributes to its anti-atherogenic effects.
Url:
DOI: 10.1038/srep24108
PubMed: 27063143
PubMed Central: 4827087
Affiliations:
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Technology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Academy of Scientific and Innovative Research</institution>, Training and Development Complex, Chennai,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vasamsetti, Sathish Babu" sort="Vasamsetti, Sathish Babu" uniqKey="Vasamsetti S" first="Sathish Babu" last="Vasamsetti">Sathish Babu Vasamsetti</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Academy of Scientific and Innovative Research</institution>, Training and Development Complex, Chennai,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gopoju, Raja" sort="Gopoju, Raja" uniqKey="Gopoju R" first="Raja" last="Gopoju">Raja Gopoju</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Academy of Scientific and Innovative Research</institution>, Training and Development Complex, Chennai,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kanugula, Anantha Koteswararao" sort="Kanugula, Anantha Koteswararao" uniqKey="Kanugula A" first="Anantha Koteswararao" last="Kanugula">Anantha Koteswararao Kanugula</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ganji, Sai Krishna" sort="Ganji, Sai Krishna" uniqKey="Ganji S" first="Sai Krishna" last="Ganji">Sai Krishna Ganji</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>National Centre for Mass Spectrometry, Indian Institute of Chemical Technology</institution>, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Prabhakar, Sripadi" sort="Prabhakar, Sripadi" uniqKey="Prabhakar S" first="Sripadi" last="Prabhakar">Sripadi Prabhakar</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>National Centre for Mass Spectrometry, Indian Institute of Chemical Technology</institution>, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Rangaraj, Nandini" sort="Rangaraj, Nandini" uniqKey="Rangaraj N" first="Nandini" last="Rangaraj">Nandini Rangaraj</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>CSIR-Centre for Cellular and Molecular Biology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Tupperwar, Nitin" sort="Tupperwar, Nitin" uniqKey="Tupperwar N" first="Nitin" last="Tupperwar">Nitin Tupperwar</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>CSIR-Centre for Cellular and Molecular Biology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kumar, Jerald Mahesh" sort="Kumar, Jerald Mahesh" uniqKey="Kumar J" first="Jerald Mahesh" last="Kumar">Jerald Mahesh Kumar</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>CSIR-Centre for Cellular and Molecular Biology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kotamraju, Srigiridhar" sort="Kotamraju, Srigiridhar" uniqKey="Kotamraju S" first="Srigiridhar" last="Kotamraju">Srigiridhar Kotamraju</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology</institution>, Uppal Road, Hyderabad, 500007,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Academy of Scientific and Innovative Research</institution>, Training and Development Complex, Chennai,<country>India</country></nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE<sup>−/−</sup> mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3 treatment not only completely reversed Mito-Esc-mediated mitochondrial biogenetic marker expressions but also caused endothelial cell death. Furthermore, Mito-Esc administration to ApoE<sup>−/−</sup> mice greatly alleviated Ang-II-induced atheromatous plaque formation, monocyte infiltration and serum pro-inflammatory cytokines levels. We conclude that Mito-Esc is preferentially taken up by the mitochondria and preserves endothelial cell survival during oxidative stress by modulating NO generation via AMPK. Also, Mito-Esc-induced SIRT3 plays a pivotal role in mediating mitochondrial biogenesis and perhaps contributes to its anti-atherogenic effects.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lusis, A J Atherosclerosis" uniqKey="Lusis A">A. J. Atherosclerosis. Lusis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Libby, P" uniqKey="Libby P">P. Libby</name></author><author><name sortKey="Ridker, P M" uniqKey="Ridker P">P. M. Ridker</name></author><author><name sortKey="Hansson, G K" uniqKey="Hansson G">G. K. 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Grotyohann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dhanasekaran, A" uniqKey="Dhanasekaran A">A. Dhanasekaran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheung, K G" uniqKey="Cheung K">K. G. Cheung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reddy, C A" uniqKey="Reddy C">C. A. Reddy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Daugherty, A" uniqKey="Daugherty A">A. Daugherty</name></author><author><name sortKey="Manning, M W" uniqKey="Manning M">M. W. Manning</name></author><author><name sortKey="Cassis, L A" uniqKey="Cassis L">L. A. Cassis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gavrila, D" uniqKey="Gavrila D">D. Gavrila</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gopal, K" uniqKey="Gopal K">K. Gopal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cacicedo, J M" uniqKey="Cacicedo J">J. M. Cacicedo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vasamsetti, S B" uniqKey="Vasamsetti S">S. B. Vasamsetti</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Inde</li></country></list><tree><country name="Inde"><noRegion><name sortKey="Karnewar, Santosh" sort="Karnewar, Santosh" uniqKey="Karnewar S" first="Santosh" last="Karnewar">Santosh Karnewar</name></noRegion><name sortKey="Ganji, Sai Krishna" sort="Ganji, Sai Krishna" uniqKey="Ganji S" first="Sai Krishna" last="Ganji">Sai Krishna Ganji</name><name sortKey="Gopoju, Raja" sort="Gopoju, Raja" uniqKey="Gopoju R" first="Raja" last="Gopoju">Raja Gopoju</name><name sortKey="Gopoju, Raja" sort="Gopoju, Raja" uniqKey="Gopoju R" first="Raja" last="Gopoju">Raja Gopoju</name><name sortKey="Kanugula, Anantha Koteswararao" sort="Kanugula, Anantha Koteswararao" uniqKey="Kanugula A" first="Anantha Koteswararao" last="Kanugula">Anantha Koteswararao Kanugula</name><name sortKey="Karnewar, Santosh" sort="Karnewar, Santosh" uniqKey="Karnewar S" first="Santosh" last="Karnewar">Santosh Karnewar</name><name sortKey="Kotamraju, Srigiridhar" sort="Kotamraju, Srigiridhar" uniqKey="Kotamraju S" first="Srigiridhar" last="Kotamraju">Srigiridhar Kotamraju</name><name sortKey="Kotamraju, Srigiridhar" sort="Kotamraju, Srigiridhar" uniqKey="Kotamraju S" first="Srigiridhar" last="Kotamraju">Srigiridhar Kotamraju</name><name sortKey="Kumar, Jerald Mahesh" sort="Kumar, Jerald Mahesh" uniqKey="Kumar J" first="Jerald Mahesh" last="Kumar">Jerald Mahesh Kumar</name><name sortKey="Prabhakar, Sripadi" sort="Prabhakar, Sripadi" uniqKey="Prabhakar S" first="Sripadi" last="Prabhakar">Sripadi Prabhakar</name><name sortKey="Rangaraj, Nandini" sort="Rangaraj, Nandini" uniqKey="Rangaraj N" first="Nandini" last="Rangaraj">Nandini Rangaraj</name><name sortKey="Tupperwar, Nitin" sort="Tupperwar, Nitin" uniqKey="Tupperwar N" first="Nitin" last="Tupperwar">Nitin Tupperwar</name><name sortKey="Vasamsetti, Sathish Babu" sort="Vasamsetti, Sathish Babu" uniqKey="Vasamsetti S" first="Sathish Babu" last="Vasamsetti">Sathish Babu Vasamsetti</name><name sortKey="Vasamsetti, Sathish Babu" sort="Vasamsetti, Sathish Babu" uniqKey="Vasamsetti S" first="Sathish Babu" last="Vasamsetti">Sathish Babu Vasamsetti</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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