title: The Small Molecule Indirubin-3'-Oxime Inhibits Protein Kinase R: Antiapoptotic and Antioxidant Effect in Rat Cardiac Myocytes.
abstract: Double-stranded, RNA-dependent protein kinase R (PKR) is a serine/threonine protein kinase activated by various stress signals. It plays an important role in inflammation, insulin sensitivity and glucose homeostasis. Increased PKR activity has been observed in obese humans as well as in obese diabetic mice. Indirubin-3'-oxime (I3O) is an effective inhibitor of cyclin-dependent kinases and glycogen synthase kinase 3-beta. However, the effects of I3O on PKR activity/expression in cultured rat cardiomyocytes have not been reported. We investigated whether I3O attenuates the effects of high glucose on PKR, oxidative stress and apoptotic gene markers. Quantitative PCR and western blotting were used to measure protein and mRNA, respectively. High glucose treatment caused significant increase in the PKR protein/mRNA expression, which was attenuated by co-treatment with I3O. High glucose-treated, cultured cardiomyocytes developed a significant increase in mRNA expression for c-Jun-N-terminal kinase, caspase-3 and NF-ĸB, which were all attenuated by pretreatment with I3O. There was also a significant increase in reactive oxygen species generation in high glucose-treated, cultured cardiomyocytes, which was attenuated by pretreatment with I3O. In conclusion, I3O may have a preventive role against the deleterious effects of high glucose in the heart.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology and Sciences Pilani, Hyderabad, Andhra Pradesh, India.
authors.forename: Mary Priyanka
authors.initials: MP
authors.lastname: Udumula
authors.forename: Brahmam
authors.initials: B
authors.lastname: Medapi
authors.forename: Indu
authors.initials: I
authors.lastname: Dhar
authors.forename: Audesh
authors.initials: A
authors.lastname: Bhat
authors.forename: Kaushik
authors.initials: K
authors.lastname: Desai
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Arti
authors.initials: A
authors.lastname: Dhar
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D032383:Myocytes, Cardiac; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D005947:Glucose; C027185:indirubin