Fenofibrate counteracts the pressure overload-induced cardiac maladaptive remodeling by protecting mitochondria

Introduction. Fenofibrate, a PPAR-α agonist used to lower serum lipid levels, reduces maladaptive cardiac remodeling and improves cardiac function with mechanisms not elucidated. This study tested the effects of fenofibrate (FFB) on the development of hypertension-associated left ventricular remodeling in the two-kidney one-clip (2K1C) rats, a model of renovascular hypertension. We focused on the expression of key regulators of mitochondrial dynamics and mitophagy/autophagy, to identify possible novel mechanisms involved in the cardioprotection of fenofibrate. Methods. The 2K1C protocol was applied to Wistar Kyoto rats by placing a silver clip on the renal artery (n=15); sham operated rats were the controls (2K0C, n=9). Four weeks after clipping, 2K1C animals were randomized to receive FFB (150 mg/kg/day. 2K1C-FFB, n=8) or vehicle (2K1C-VEH, n=7), for 8 weeks. For all analyses, before drug administration, Helmert “a priori” orthogonal contrast was used to compare sham-operated vs 2K1C group to assess the effect of 4 weeks of renal clip, and 2K1C-VEH vs 2K1C-FFB to check for unbiased group randomization. At 12 weeks, systolic pressure and cardiac functional parameters were assessed, by tail-cuff plethysmography and cardiac magnetic resonance imaging, respectively. Cardiomyocyte size and protein expression of mediators of hypertrophy and mitochondrial dynamics were examined by histology and western blot analysis. To evaluate whether fenofibrate directly protects cardiomyocytes against stress-induced hypertrophy independently from hypertension, an in vitro model, using H9C2 cardiomyocytes stimulated with Ang II, was used. Results. In 2K1C rats, FFB counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and size of cardiomyocytes. FFB rebalanced the expression of the mitochondrial protein Mfn2, Drp1 and Parkin, which regulate fusion, fission and mitophagy, respectively. In addition, FFB promoted the conversion of LC3 I to LC3 II, while decreased the expression of p62, suggesting an enhanced autophagic response. In H9C2 cells, FFB reversed the Ang II-induced up-regulation of hypertrophic markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane. Relevantly, FFB restored the expression of the Uncoupling protein 2 (UCP2), an up-stream regulator of Parkin, Mfn2 and Drp1, both in our in vivo and in vitro models. Conclusion. This study demonstrates, for the first time, that FFB counteracts cardiac remodeling caused by renovascular hypertension. The cardioprotective effects are partially due to an improvement of the impaired mitochondrial fusion and fission, and on enhanced mitophagy by activation of AMPK/mTORC1 pathway and by enhancing UCP2 expression. These findings support the repurposing of FFB for the treatment of cardiac hypertrophy and provide new potential targets that mediates its pharmacological function.