title: Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis.
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.
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.|Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Karnewar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.|Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
authors.forename: Sathish Babu
authors.initials: SB
authors.lastname: Vasamsetti
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.|Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
authors.forename: Raja
authors.initials: R
authors.lastname: Gopoju
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
authors.forename: Anantha Koteswararao
authors.initials: AK
authors.lastname: Kanugula
authors.affiliation: National Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad, 500007, India.
authors.forename: Sai Krishna
authors.initials: SK
authors.lastname: Ganji
authors.affiliation: National Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad, 500007, India.
authors.forename: Sripadi
authors.initials: S
authors.lastname: Prabhakar
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500007, India.
authors.forename: Nandini
authors.initials: N
authors.lastname: Rangaraj
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500007, India.
authors.forename: Nitin
authors.initials: N
authors.lastname: Tupperwar
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500007, India.
authors.forename: Jerald Mahesh
authors.initials: JM
authors.lastname: Kumar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.|Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014468:Umbelliferones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D034741:RNA, Small Interfering; D014468:Umbelliferones; D000804:Angiotensin II; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; D055372:AMP-Activated Protein Kinases; D056566:Sirtuin 3; C007628:esculetin; D019331:NG-Nitroarginine Methyl Ester