Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara, Jalisco, México.
University of Guadalajara, IIRSME, CUCS, Guadalajara, Jalisco, México.
Cardiovasc Drugs Ther. 2021 Oct;35(5):927-938. doi: 10.1007/s10557-020-07014-9.
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.
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.
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.
The results suggest that PR-PFD could be a promising drug for the prevention and treatment of cardiac steatosis and fibrosis induced by obesity.
肥胖与全身胰岛素抵抗和心肌肥厚伴纤维化有关。过氧化物酶体增殖物激活受体（PPARs）调节碳水化合物和脂质代谢，提高胰岛素敏感性、甘油三酯水平、炎症和氧化应激。我们之前证明，持续释放吡非尼酮（PR-PFD）是 Pparα 的激动性配体，具有抗炎和抗纤维化作用，可能是治疗心脏疾病的有前途的药物。在这里，我们研究了 PR-PFD 在高脂肪/高碳水化合物（HFHC）饮食诱导的非酒精性脂肪性肝炎（NASH）和肥胖小鼠心室组织中的作用。
5 只雄性 C57BL/6 J 小鼠给予正常饮食（ND），10 只给予 HFHC 饮食 16 周；在喂养 8 周时，5 只 HFHC 饮食的小鼠给予 PR-PFD（350mg/kg/天）与 HFHC 饮食混合。
PR-PFD 可预防全身胰岛素抵抗、心脏重量/体重比、心肌脂肪变性伴炎症灶、肥大和纤维化。此外，HFHC 小鼠的结蛋白、Tgfβ1、Timp1、I 型胶原（Col I）、III 型胶原（Col III）、TNF-α 和 Nrf2mRNA 水平明显升高，与 ND 心室组织相比，α-SMA、NF-κB、Nrf2、肌钙蛋白 I、Acox1、Cpt1A 和 Lxrα 蛋白水平也明显升高。在机制上，PR-PFD 治疗的 HFHC 小鼠显著降低了 HFHC 饮食引起的这些基因的过度表达。此外，PR-PFD 还过表达 Pgc1a mRNA 水平以及 Pparα、Pparγ、Acox1 和 Cpt1A 蛋白水平。
结果表明，PR-PFD 可能是预防和治疗肥胖引起的心脏脂肪变性和纤维化的有前途的药物。
