Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: Potential implications in atherosclerosis

Santosh Karnewar, Sathish Babu Vasamsetti, Raja Gopoju, Anantha Koteswararao Kanugula, Sai Krishna Ganji, Sripadi Prabhakar, Nandini Rangaraj, Nitin Tupperwar, Jerald Mahesh Kumar, Srigiridhar Kotamraju

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish
Article number24108
JournalScientific Reports
Volume6
DOIs
StatePublished - 11 Apr 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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