Jorge Gutiérrez-Cuevas1, Ana Sandoval-Rodríguez1, Hugo Christian Monroy-Ramírez1, Monica Vazquez-Del Mercado2, Arturo Santos-García3, Juan Armendáriz-Borunda4,5. 1. Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara, Jalisco, México. 2. University of Guadalajara, IIRSME, CUCS, Guadalajara, Jalisco, México. 3. Tecnologico de Monterrey, Campus Guadalajara, Guadalajara, Jalisco, México. 4. Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara, Jalisco, México. armdbo@gmail.com. 5. Tecnologico de Monterrey, Campus Guadalajara, Guadalajara, Jalisco, México. armdbo@gmail.com.
Abstract
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.
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.
Authors: Shuyun Rao; Xiaochun Yang; Kazufumi Ohshiro; Sobia Zaidi; Zhanhuai Wang; Kirti Shetty; Xiyan Xiang; Md Imtaiyaz Hassan; Taj Mohammad; Patricia S Latham; Bao-Ngoc Nguyen; Linda Wong; Herbert Yu; Yousef Al-Abed; Bibhuti Mishra; Michele Vacca; Gareth Guenigault; Michael E D Allison; Antonio Vidal-Puig; Jihane N Benhammou; Marcus Alvarez; Päivi Pajukanta; Joseph R Pisegna; Lopa Mishra Journal: Sci Transl Med Date: 2021-12-15 Impact factor: 17.956