Nanotized PPARα Overexpression Targeted to Hypertrophied Myocardium Improves Cardiac Function by Attenuating the p53-GSK3β-Mediated Mitochondrial Death Pathway

Aims: Metabolic remodeling of cardiac muscles during pathological hypertrophy is characterized by downregulation of fatty acid oxidation (FAO) regulator, peroxisome proliferator-activated receptor alpha (PPAR alpha). Thereby, we hypothesized that a cardiac-specific induction of PPAR alpha might restore the FAO-related protein expression and resultant energy deficit. In the present study, consequences of PPAR alpha augmentation were evaluated for amelioration of chronic oxidative stress, myocyte apoptosis, and cardiac function during pathological cardiac hypertrophy. Results: Nanotized PPAR overexpression targeted to myocardium was done by a stearic acid-modified carboxymethyl-chitosan (CMC) conjugated to a 20-mer myocyte-targeted peptide (CMCP). Overexpression of PPAR alpha ameliorated pathological hypertrophy and improved cardiac function. Augmented PPAR alpha in hypertrophied myocytes revealed downregulated p53 acetylation (lys 382), leading to reduced apoptosis. Such cells showed increased binding of PPAR alpha with p53 that in turn reduced interaction of p53 with glycogen synthase kinase-3 beta (GSK3 beta), which upregulated inactive phospho-GSK3 beta (serine [Ser]9) expression within mitochondrial protein fraction. Altogether, the altered molecular milieu in PPAR alpha-overexpressed hypertrophy groups restored mitochondrial structure and function both in vitro and in vivo. Innovation: Cardiomyocyte-targeted overexpression of a protein of interest (PPAR alpha) by nanotized plasmid has been described for the first time in this study. Our data provide a novel insight towards regression of pathological hypertrophy by ameliorating mitochondrial oxidative stress in targeted PPAR alpha-overexpressed myocardium. Conclusion:PPAR alpha-overexpression during pathological hypertrophy showed substantial betterment of mitochondrial structure and function, along with downregulated apoptosis. Myocardium-targeted overexpression of PPAR alpha during pathological cardiac hypertrophy led to an overall improvement of cardiac energy deficit and subsequent cardiac function, thereby, opening up a potential avenue for cardiac tissue engineering during hypertrophic cardiac pathophysiology.