title: Mitochondria-targeted esculetin inhibits PAI-1 levels by modulating STAT3 activation and miR-19b via SIRT3: Role in acute coronary artery syndrome.
abstract: In this study we explored the microRNAs responsible for the regulation of PAI-1 during LPS-stimulated inflammation in human aortic endothelial cells and subsequently studied the effect of a newly synthesized mitochondria-targeted esculetin (Mito-Esc) that was shown for its anti-atherosclerotic potential, in modulating PAI-1 levels and its targeted miRs during angiotensin-II-induced atherosclerosis in ApoE-/-mice. LPS-stimulated PAI-1 was accompanied with an upregulation of miR-19b and down-regulation of miR-30c. These effects of LPS on PAI-1 were reversed in the presence of both parent esculetin and Mito-Esc. However, the effect of Mito-Esc was more pronounced in the regulation of PAI-1. In addition, LPS-stimulated PAI-1 expression was significantly decreased in cells treated with Anti-miR-19b, thereby suggesting that miR-19b co-expression plays a key role in PAI-1 regulation. The results also show that incubation of cells with Stattic, an inhibitor of STAT-3, inhibited LPS-stimulated PAI-1 expression. Interestingly, knockdown of SIRT3, a mitochondrial biogenetic marker, enhanced PAI-1 levels via modulation of miR-19b and -30c. Mito-Esc treatment significantly inhibited Ang-II-induced PAI-1, possibly via altering miR-19b and 30c in ApoE-/-mice. The association between PAI-1, miR-19b and -30c were further confirmed in plasma and microparticles isolated from patients suffering from acute coronary syndrome of various degrees. Taken together, LPS-induced PAI-1 involves co-expression of miR-19b and down regulation of miR-30c, and Mito-Esc treatment by modulating miR-19b and miR-30c through SIRT3 activation, inhibits PAI-1 levels that, in part, contribute to its anti-atherosclerotic effects. Moreover, there exists a strong positive correlation between miR-19b and PAI-1 in patients suffering from ST-elevated myocardial infarction.
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Sujana
authors.initials: S
authors.lastname: Katta
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.|Academy of Scientific and Innovative Research, Training and Development Complex, CSIR Campus, Taramani, Chennai, Tamilnadu, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Karnewar
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Devayani
authors.initials: D
authors.lastname: Panuganti
authors.affiliation: CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
authors.forename: Mahesh Kumar
authors.initials: MK
authors.lastname: Jerald
authors.affiliation: Department of Cardiology, CARE Hospitals and CARE Foundation, Hyderabad, India.
authors.forename: B K S
authors.initials: BKS
authors.lastname: Sastry
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.|Academy of Scientific and Innovative Research, Training and Development Complex, CSIR Campus, Taramani, Chennai, Tamilnadu, India.
authors.forename: Srigiridhar
authors.identifier: http://orcid.org/0000-0003-0525-7553
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D000072657:ST Elevation Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D008070:Lipopolysaccharides; C549214:MIRN19A microRNA, human; C561642:MIRN19 microRNA, mouse; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C525046:Sirt3 protein, mouse; C494087:Stat3 protein, mouse; D014468:Umbelliferones; C466093:SIRT3 protein, human; D056566:Sirtuin 3; C007628:esculetin
keywords: Mitochondria-targeted esculetin; PAI-1; SIRT3; acute coronary artery syndrome; miR-19b