PGC-1α Agonist Rescues Doxorubicin-Induced Cardiomyopathy by Mitigating the Oxidative Stress and Necroptosis.

Abstract

Cardiomyopathy (particularly dilated cardiomyopathy (DCM)) significantly contributes to development and progression of heart failure (HF), and inflammatory factors further deteriorate the symptoms. Morphological and functional defects of the heart in doxorubicin (DOX)-induced cardiomyopathy (cardiotoxicity) are similar to those of DCM. We used anagonist of PGC-1α (PPAR (peroxisome proliferator-activated receptor-gamma)-γ coactivator-1α) that is considered as the 'master regulator' of mitochondrial biogenesis with an aim to rescue the DOX-induced deleterious effects on the heart. Forty male C57BL/6J mice (8 weeks old) were divided in four groups, Control, DOX, ZLN005, and ZLN005 + DOX (n = 10 each group). The DOX-induced (10 mg/kg, single dose) cardiomyopathy mimics a DCM-like phenotype with marked morphologic alteration in cardiac tissue and functional derangements. Significant increased staining was observed for Masson Trichrome/Picrosirius red and α-Smooth Muscle Actinin (α-SMA) that indicated enhanced fibrosis in the DOX group compared to the control that was attenuated by (peroxisome proliferator-activated receptor-gamma (PPAR-γ) coactivator) (PGC)-1α (alpha) agonist (four doses of 2.5 mg/kg/dose; cumulative dose = 10 mg/kg). Similarly, elevated expression of necroptosis markers along with enhanced oxidative stress in the DOX group were alleviated by PGC-1α agonist. These data collectively suggested the potent therapeutic efficacy of PGC-1α agonist in mitigating the deleterious effects of DOX-induced cardiomyopathy, and it may be targeted in developing the future therapeutics for the management of DCM/HF.

• Authors: Shipra, Manoj Kumar Tembhre, Milind Padmakar Hote, Neetu Bhari, Ramakrishnan Lakshmy, S Senthil Kumaran
• Journal: Antioxidants (Basel, Switzerland) (Antioxidants (Basel)) Vol. 12 Issue 9 (Sep 05 2023) ISSN: 2076-3921 [Print] Switzerland
• PMID: 37760023 (Publication Type: Journal Article)