Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Abstract

Background Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Methods Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. Results After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. Conclusions Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice

“…The protective effects of PEM have been documented in extrahepatic organs both in mouse experiments and in the clinical setting. For example, PEM promoted ischemia-induced revascularization through eNOS-dependent mechanisms in mice [ 35 , 36 ]. PEM also attenuated neointima formation after vascular injury in mice fed normal chow and a high-fat diet [ 36 , 37 , 38 ].…”

“…For example, PEM promoted ischemia-induced revascularization through eNOS-dependent mechanisms in mice [ 35 , 36 ]. PEM also attenuated neointima formation after vascular injury in mice fed normal chow and a high-fat diet [ 36 , 37 , 38 ]. However, according to the results of the current study, those favorable PEM effects may not have been caused by the direct activation of PPARα in extrahepatic tissues, such as the endothelium and vascular tissue.…”

LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats

“…Systolic blood pressure and pulse rate were measured at 0, 11 and 18 days using tail-cuff plethysmography (MK-2000, Muromachi, Tokyo, Japan) 41 . An average of three measurements was used.…”

Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy

“…Honda et al revealed that pemafibrate attenuated hepatic triglyceride contents, macrophage infiltration, and hepatic fibrosis in a diet-induced steatohepatitis model 19 . Yoshida et al also reported that pemafibrate and statins improved vascular endothelial dysfunction in dahl/salt-sensitive rats 20 . Although a previous report indicated that another fibrate, fenofibrate, had a protective role against cardiac injury in a porcine myosin-induced rat myocarditis model 21 , no study has investigated whether pemafibrate might regulate cardiac inflammation or cholesterol metabolism in the heart.…”