title: Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment.
abstract: Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy.
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700 019, West Bengal, India. Electronic address: aramitaray@yahoo.co.in.
authors.forename: Aramita
authors.initials: A
authors.lastname: Ray
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700 019, West Bengal, India. Electronic address: rana.santanu@gmail.com.
authors.forename: Santanu
authors.initials: S
authors.lastname: Rana
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700 019, West Bengal, India. Electronic address: durba.research@gmail.com.
authors.forename: Durba
authors.initials: D
authors.lastname: Banerjee
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700 019, West Bengal, India. Electronic address: arkadeep.mitra@gmail.com.
authors.forename: Arkadeep
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700 019, West Bengal, India. Electronic address: rdatta30@gmail.com.
authors.forename: Ritwik
authors.initials: R
authors.lastname: Datta
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700 019, West Bengal, India. Electronic address: shaon.me@gmail.com.
authors.forename: Shaon
authors.initials: S
authors.lastname: Naskar
authors.affiliation: Genetics and Molecular Cardiology Laboratory, Department of Zoology, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700 019, West Bengal, India. Electronic address: sagartirtha.sarkar@gmail.com.
authors.forename: Sagartirtha
authors.initials: S
authors.lastname: Sarkar
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001682:Biological Availability; D006332:Cardiomegaly / Q000188:drug therapy*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000031:analogs & derivatives / Q000737:chemistry; D003474:Curcumin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D016503:Drug Delivery Systems; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C514968:carboxymethyl-chitosan; D045304:Cytochromes c; D048271:Chitosan; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D003474:Curcumin
keywords: Cardiac hypertrophy; Cardiomyocyte apoptosis; Cardiomyocyte targeted delivery; Curcumin; p53 ubiquitination; p53–p300 interaction