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.
Highlights
Cardiomyocyte hypertrophy appears as an adaptive process under hypoxia in order to meet the increased oxygen demand and maintain homeostasis, prolonged oxidative stress might induce physiological events [1,2]
human ventricular cardiomyocytes (HVCM) cells exposed to hypoxia showed increment in cell size by 18%, increment in amino acid uptake by 73% and up-regulation of atrial natriuretic factor (ANF) levels by 2.9 times after 24 h of hypoxia exposure compared to normoxia control cells
Treatment of cardiomyocytes with nanocurcumin after 24 h of hypoxia reduced cell size by 38%, amino acid uptake by 42.8% and ANF levels by 64%(as observed in Fig 2D) compared to cells exposed to hypoxia only
Summary
Cardiomyocyte hypertrophy appears as an adaptive process under hypoxia in order to meet the increased oxygen demand and maintain homeostasis, prolonged oxidative stress might induce (patho-) physiological events [1,2]. Histone acetylation by p-300 HAT promotes transcription of the DNA and activates hypertrophic gene expression [4]. Hypertrophy remains an acclimatizing strategy of cardiomyocytes under hypoxia, sustained oxidative stress is known to induce cytological damages at least in part, by activating cascade of stress-responsive events including mitochondrial damage, redox imbalance and apoptotic cell death [7,8,9,10,11,12]. Hypoxia induced cardiomyocyte damage is inevitably associated with disruption of mitochondrial function and induction of programmed cell death or apoptosis [13,14]. Since preservation of mitochondrial function is critical to cardiac performance, it is important to assess the changes in mitochondrial homeostasis under stress [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
