Department of Pharmaceutical Sciences, University of Milan, Milan, Italy.
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Eur J Pharmacol. 2024 Sep 5;978:176767. doi: 10.1016/j.ejphar.2024.176767. Epub 2024 Jun 21.
Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function.
非诺贝特是一种临床上用于降低血清脂质水平的 PPAR-α 激动剂，可减轻心脏重构并改善心功能。然而，其作用机制尚不完全清楚。在这项研究中，我们研究了非诺贝特在肾血管性高血压大鼠模型中对线粒体的影响，重点研究了控制线粒体动力学和自噬的介质。用二肾一夹（2K1C）高血压大鼠给予非诺贝特 150mg/kg/天（2K1C-FFB）或载体（2K1C-VEH）治疗 8 周。通过体内评估收缩压和心功能，通过组织学和 Western blot 分析对心肌细胞大小和心脏肥大及线粒体动力学介质的蛋白表达进行体外检测。非诺贝特治疗可逆转高血压的发展和左心室质量、相对壁厚度和心肌细胞横截面积的增加。此外，非诺贝特重新平衡了融合调节剂 Mfn2、分裂调节剂 Drp1 和 Parkin 的表达。关于自噬，LC3-II/LC3-I 比值在 2K1C-VEH 和 2K1C-FFB 中增加，而自噬仅在 2K1C-FFB 中增加。在培养的 H9C2 心肌细胞中，非诺贝特逆转了 Ang II 诱导的肥大标志物 Nppa 和 Myh7 的 mRNA 上调、活性氧的积累和线粒体膜的去极化，通过上调解偶联蛋白 2 发挥保护作用。我们的结果表明，非诺贝特直接作用于心肌细胞，可对抗压力超负荷引起的心脏适应性重构不良。本研究揭示了一个迄今隐藏的机制，涉及线粒体动力学在非诺贝特有益作用中的作用，支持其重新用于治疗心脏肥大，并为其药理功能提供新的潜在靶点。
