title: Nanocurcumin Prevents Hypoxia Induced Stress in Primary Human Ventricular Cardiomyocytes by Maintaining Mitochondrial Homeostasis.
abstract: Hypoxia induced oxidative stress incurs pathophysiological changes in hypertrophied cardiomyocytes by promoting translocation of p53 to mitochondria. Here, we investigate the cardio-protective efficacy of nanocurcumin in protecting primary human ventricular cardiomyocytes (HVCM) from hypoxia induced damages. Hypoxia induced hypertrophy was confirmed by FITC-phenylalanine uptake assay, atrial natriuretic factor (ANF) levels and cell size measurements. Hypoxia induced translocation of p53 was investigated by using mitochondrial membrane permeability transition pore blocker cyclosporin A (blocks entry of p53 to mitochondria) and confirmed by western blot and immunofluorescence. Mitochondrial damage in hypertrophied HVCM cells was evaluated by analysing bio-energetic, anti-oxidant and metabolic function and substrate switching form lipids to glucose. Nanocurcumin prevented translocation of p53 to mitochondria by stabilizing mitochondrial membrane potential and de-stressed hypertrophied HVCM cells by significant restoration in lactate, acetyl-coenzyme A, pyruvate and glucose content along with lactate dehydrogenase (LDH) and 5' adenosine monophosphate-activated protein kinase (AMPKα) activity. Significant restoration in glucose and modulation of GLUT-1 and GLUT-4 levels confirmed that nanocurcumin mediated prevention of substrate switching. Nanocurcumin prevented of mitochondrial stress as confirmed by c-fos/c-jun/p53 signalling. The data indicates decrease in p-300 histone acetyl transferase (HAT) mediated histone acetylation and GATA-4 activation as pharmacological targets of nanocurcumin in preventing hypoxia induced hypertrophy. The study provides an insight into propitious therapeutic effects of nanocurcumin in cardio-protection and usability in clinical applications.
authors.affiliation: Experimental Biology Division, Department of Experimental Biology, Defence Institute of Physiology and Allied Science, Defence Research and Development Organization, Timarpur, New Delhi, India.
authors.forename: Sarita
authors.initials: S
authors.lastname: Nehra
authors.affiliation: Experimental Biology Division, Department of Experimental Biology, Defence Institute of Physiology and Allied Science, Defence Research and Development Organization, Timarpur, New Delhi, India.
authors.forename: Varun
authors.initials: V
authors.lastname: Bhardwaj
authors.affiliation: Experimental Biology Division, Department of Experimental Biology, Defence Institute of Physiology and Allied Science, Defence Research and Development Organization, Timarpur, New Delhi, India.
authors.forename: Lilly
authors.initials: L
authors.lastname: Ganju
authors.affiliation: Experimental Biology Division, Department of Experimental Biology, Defence Institute of Physiology and Allied Science, Defence Research and Development Organization, Timarpur, New Delhi, India.
authors.forename: Deepika
authors.initials: D
authors.lastname: Saraswat
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology; D051548:Histone Acetyltransferases / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; C495677:SLC2A1 protein, human; C495680:SLC2A2 protein, human; D016159:Tumor Suppressor Protein p53; D019344:Lactic Acid; D016572:Cyclosporine; D051548:Histone Acetyltransferases; D055372:AMP-Activated Protein Kinases; D003474:Curcumin; D005947:Glucose