Prolonged-release pirfenidone prevents obesity-induced cardiac steatosis and fibrosis in a mouse NASH model

• Published in: Cardiovascular drugs and therapy 2021-10, Vol.35 (5), p.927-938
• Main Authors: Gutiérrez-Cuevas, Jorge, Sandoval-Rodríguez, Ana, Monroy-Ramírez, Hugo Christian, Vazquez-Del Mercado, Monica, Santos-García, Arturo, Armendáriz-Borunda, Juan
• Format: Article
• Language: English
• Subjects: Animal tissues; Animals; Body weight; Body Weight - drug effects; Calcium-binding protein; Carbohydrate metabolism; Carbohydrates; Cardiology; Collagen; Collagen (type I); Collagen (type III); Coronary artery disease; Desmin; Diet; Diet, High-Fat; Disease Models, Animal; Fibrosis; Fibrosis - physiopathology; Fibrosis - prevention & control; Heart diseases; Heart Diseases - physiopathology; Heart Diseases - prevention & control; High carbohydrate diet; High fat diet; Hypertrophy; Inflammation; Insulin; Insulin resistance; Insulin Resistance - physiology; Lipid metabolism; Lipids; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; mRNA; NF-κB protein; Non-alcoholic Fatty Liver Disease - physiopathology; Obesity; Obesity - physiopathology; Organ Size - drug effects; Original Article; Oxidative stress; Peroxisome proliferator-activated receptors; PPAR alpha - agonists; Proteins; Pyridones - pharmacology; Random Allocation; Steatosis; Tissue inhibitor of metalloproteinase 1; Transforming growth factor-b1; Triglycerides; Troponin; Troponin I; Ventricle
• ISSN: 0920-3206; 1573-7241
• DOI: 10.1007/s10557-020-07014-9

Purpose Obesity is associated with systemic insulin resistance and cardiac hypertrophy with fibrosis. Peroxisome proliferator-activated receptors (PPARs) regulate carbohydrate and lipid metabolism, improving insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. We previously demonstrated that prolonged-release pirfenidone (PR-PFD) is an agonistic ligand for Pparα with anti-inflammatory and anti-fibrotic effects, and might be a promising drug for cardiac diseases-treatment. Here, we investigated the effects of PR-PFD in ventricular tissue of mice with nonalcoholic steatohepatitis (NASH) and obesity induced by high-fat/high-carbohydrate (HFHC) diet. Methods Five male C57BL/6 J mice were fed with normal diet (ND) and ten with HFHC diet for 16 weeks; at 8 weeks of feeding, five mice with HFHC diet were administered PR-PFD (350 mg/kg/day) mixed with HFHC diet. Result Systemic insulin resistance, heart weight/body weight ratio, myocardial steatosis with inflammatory foci, hypertrophy, and fibrosis were prevented by PR-PFD. In addition, HFHC mice showed significantly increased desmin, Tgfβ1, Timp1, collagen I (Col I), collagen III (Col III), TNF-α, and Nrf2 mRNA levels, including α-SMA, NF-kB, Nrf2, troponin I, Acox1, Cpt1A, and Lxrα protein levels compared with the ND ventricular tissues. Mechanistically, HFHC mice with PR-PFD treatment significantly decreased these genes overexpressed by HFHC diet. Furthermore, PR-PFD overexpressed the Pgc1a mRNA levels and Pparα, Pparγ, Acox1, and Cpt1A protein levels. Conclusions The results suggest that PR-PFD could be a promising drug for the prevention and treatment of cardiac steatosis and fibrosis induced by obesity.