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Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: potential implications in atherosclerosis.
Karnewar, Santosh; Vasamsetti, Sathish Babu; Gopoju, Raja; Kanugula, Anantha Koteswararao; Ganji, Sai Krishna; Prabhakar, Sripadi; Rangaraj, Nandini; Tupperwar, Nitin; Kumar, Jerald Mahesh; Kotamraju, Srigiridhar.
Afiliación
  • Karnewar S; Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
  • Vasamsetti SB; Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
  • Gopoju R; Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
  • Kanugula AK; Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
  • Ganji SK; Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
  • Prabhakar S; Academy of Scientific and Innovative Research, Training and Development Complex, Chennai, India.
  • Rangaraj N; Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Hyderabad, 500007, India.
  • Tupperwar N; National Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad, 500007, India.
  • Kumar JM; National Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad, 500007, India.
  • Kotamraju S; CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500007, India.
Sci Rep ; 6: 24108, 2016 Apr 11.
Article en En | MEDLINE | ID: mdl-27063143
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.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Umbeliferonas / Proteínas Quinasas Activadas por AMP / Sirtuina 3 / Mitocondrias / Óxido Nítrico / Antioxidantes Tipo de estudio: Etiology_studies Idioma: En Revista: Sci Rep Año: 2016 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Umbeliferonas / Proteínas Quinasas Activadas por AMP / Sirtuina 3 / Mitocondrias / Óxido Nítrico / Antioxidantes Tipo de estudio: Etiology_studies Idioma: En Revista: Sci Rep Año: 2016 Tipo del documento: Article