Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

• Published in: Toxicology and applied pharmacology Vol. 290; pp. 54 - 65
• Main Authors: Ray, Aramita, Rana, Santanu, Banerjee, Durba, Mitra, Arkadeep, Datta, Ritwik, Naskar, Shaon, Sarkar, Sagartirtha
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2016
• Subjects: 60 APPLIED LIFE SCIENCES; Acetylation; AMINO ACIDS; ANGIOTENSIN; Animals; Apoptosis - drug effects; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Biological Availability; Cardiac hypertrophy; Cardiomegaly - drug therapy; Cardiomyocyte apoptosis; Cardiomyocyte targeted delivery; Caspase 3 - genetics; Caspase 3 - metabolism; Cell Survival - drug effects; Chitosan - analogs & derivatives; Chitosan - chemistry; Curcuma longa; CURCUMIN; Curcumin - administration & dosage; Curcumin - pharmacokinetics; CYTOCHROMES; Cytochromes c - genetics; Cytochromes c - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Drug Delivery Systems; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; HYPERTROPHY; LYMPHOMAS; MYOCARDIUM; Myocardium - pathology; Myocytes, Cardiac - drug effects; MYOSIN; NANOPARTICLES; Nanoparticles - chemistry; OLIGOSACCHARIDES; OXIDASES; p53 ubiquitination; p53–p300 interaction; PEPTIDES; POLYMERASES; RATS; Rats, Wistar; Rattus norvegicus; RIBOSE; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Cardiomyocyte targeted delivery; AngIIMG; C; PCNA; RPL32; AngIICur; EDC; H; PARP; HCur5mg; AngIICurNP; AngIICurNP+MG; HCur35mg; HW; TUNEL; BW; AngIIC646; CMC; NHS; HCurNP; Curcumin; AngII; Con; P-p65-NFκB; IP; Cardiac hypertrophy; P-p53; PC; BOC2O; NC; Ac-p53; COX IV; p53–p300 interaction; Bax; Bcl2; ANF; βMHC; p65-NFκB; Cardiomyocyte apoptosis; p53 ubiquitination; NL
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.11.011

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 5mg/kg body weight compared to free Curcumin at 35mg/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. •Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug.•Curcumin nanoparticle regresses cardiac hypertrophy by reducing myocyte apoptosis.•Targeted Curcumin shows higher efficacy over free Curcumin to regress hypertrophy.•Curcumin modulates p300-HAT axis to facilitate p53 degradation.