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Combination Therapy with Pemafibrate (K-877)

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Combination Therapy with Pemafibrate (K-877) Yoshida et al. Cardiovasc Diabetol (2020) 19:149 https://doi.org/10.1186/s12933-020-01132-2 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Combination therapy with pemafbrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet Masatoki Yoshida1, Kazufumi Nakamura1* , Toru Miyoshi1, Masashi Yoshida1, Megumi Kondo1, Kaoru Akazawa1, Tomonari Kimura1, Hiroaki Ohtsuka1, Yuko Ohno1,2, Daiji Miura3 and Hiroshi Ito1 Abstract Background: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) choles- terol levels. Pemafbrate (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 pemafbrate improves the progression of atherosclerosis. The aim of this study was to assess the efect of combination therapy with pitavastatin and pemaf- brate on lipid profles 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 fve 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 pemafbrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafbrate) 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 signifcantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafbrate signifcantly 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 treat- ment. 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 signifcantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafbrate group signifcantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates sig- nifcantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafbrate group and the HD-combination group compared with the HD- vehicle group. However, the expression levels did not respond signifcantly to pitavastatin alone. *Correspondence: [email protected] 1 Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan Full list of author information is available at the end of the article © The Author(s) 2020, corrected publication 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yoshida et al. Cardiovasc Diabetol (2020) 19:149 Page 2 of 10 Conclusions: Combination therapy with pitavastatin and pemafbrate improved lipid profles and endothelial dys- function in hypertension and insulin resistance model rats. Pemafbrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression. Keywords: Pemafbrate, Statin, Endothelial function Background follow-up [19]. Tese fndings suggest that re-evalua- Many clinical trials and meta-analyses have revealed tion of TG-lowering therapy as an add-on strategy to that treatment with statins, which are 3-hydroxy-meth- statins is needed. ylglutaryl coenzyme A (HMG-CoA) reductase inhibi- Fibrates activate a transcription factor that belongs to tors, targets a reduction in low-density lipoprotein the nuclear receptor superfamily, peroxisome prolifer- cholesterol (LDL-C) and thereby decreases the risk of ator-activated receptor α (PPARα), and controls lipid coronary heart disease (CHD) and all-cause mortal- metabolism. Recently, pemafbrate (K-877), a novel selec- ity [1]. However, many CHD cases are not prevented tive PPARα modulator (SPPARMα), has been developed and the residual risk factors including high triglycer- [20], which is even more potent than fenofbric acid (the ide (TG) and low high-density lipoprotein cholesterol active metabolite of fenofbrate) and more specifc for (HDL-C) levels remain unsettled [2]. human PPARα than either PPARγ or δ [21]. Fasting and non-fasting hypertriglyceridemia is a Pemafbrate robustly decreases serum TG levels in fast- risk factor for CHD [3–5]. Several mechanisms of ing and non-fasting or postprandial states and increases atherogenesis in hypertriglyceridemia are proposed. serum HDL-C levels [22, 23]. Moreover, pemafbrate Hypertriglyceridemia is involved in the production of was superior to fenofbrate in terms of serum TG-low- proinfammatory cytokines, recruitment of neutro- ering efect and hepatic and renal safety [22]. Te ongo- phils, and generation of oxidative stress, resulting in ing PROMINENT trial is ongoing in patients with type 2 endothelial dysfunction [6–9]. Endothelial dysfunction diabetes mellitus, elevated TG, and low levels of HDL-C is an initial process of atherogenesis, and it contrib- to determine whether treatment with pemafbrate safely utes to the pathogenesis of CHD. Among TG-rich lipo- reduces residual cardiovascular risk. Terefore, we proteins, remnant lipoproteins depress the activity of hypothesized that combination therapy with a statin plus endothelial nitric oxide synthase (eNOS) in endothelial pemafbrate could notably improve endothelial dysfunc- cells and decrease nitric oxide (NO) released from the tion in metabolic syndrome. Te aim of this study was to endothelium [10, 11]. assess the efect of combination therapy with pitavasta- Endothelial dysfunction assessed by brachial artery tin and pemafbrate on lipid profles and endothelial dys- fow-mediated dilatation (FMD) has been shown to function in Dahl salt-sensitive (DS) rats fed a high-salt be impaired in patients with traditional coronary risk and high-fat diet, which showed hypertension and insulin factors, including hypertension, dyslipidemia, diabetes resistance [24, 25]. mellitus, and smoking, and it has been considered to be a cause of atherosclerosis [5, 6, 12–14]. Statins improve Methods endothelial function as assessed by FMD [15, 16]. In Protocols for animal experiments addition, hypertriglyceridemia is independently associ- Seven-week-old male Dahl salt-sensitive (DS) rats ated with endothelial dysfunction as assessed by FMD (n = 44) (Japan SLC, Shizuoka, Japan) were fed a normal in patients with CHD during statin therapy [17]. diet (ND; 0.3% NaCl and 4.5% fat) (CE-2, CLEA Japan, Previously, a clinical trial for combination therapy Inc., Tokyo, Japan) or a high-salt and high-fat diet (HD; with a statin plus a fbrate to reduce the residual risk 8% NaCl and 29.4% fat) (CLEA Japan), as previously was conducted in patients with type 2 diabetes mellitus. described [26], and they were treated with a vehicle (0.5% Te ACCORD study showed that combination therapy carboxy methyl cellulose and 0.5% methyl cellulose), pita- with simvastatin plus fenofbrate did not reduce car- vastatin (0.3 mg/kg/day) (Kowa Co., Ltd., Tokyo, Japan), diovascular outcomes and mortality compared with pemafbrate (K-877) (0.5 mg/kg/day) (Kowa Co., Ltd.) simvastatin alone [18]. However, in a preplanned sub- or a combination of pitavastatin (0.3 mg/kg/day) and group analysis, there was a trend beneft of fenofbrate pemafbrate (K-877) (0.5 mg/kg/day) (Fig. 1) by oral gav- in patients with a high TG level (≥ 204 mg/dL) or a low age for a period of 12 weeks (Fig. 1). Body weight was HDL-C level (≤ 34 mg/dL) [2]. Additionally, fbrate measured once a week for a period of 12 weeks. Rats treatment during the trial period was associated with were divided into the following fve groups: (1) ND- a legacy efect of improved survival over a post-trial vehicle group (n = 5) fed an ND and treated with vehicle; Yoshida et al. Cardiovasc Diabetol (2020) 19:149 Page 3 of 10 Vascular relaxation studies Normal diet (0.3% NaCl and 4.5% fat) [Group] Endothelium-dependent relaxation in response to ace- [ND-vehicle] Vehicle tylcholine was evaluated. At 19 weeks, rats were anes- High-salt and high-fat diet (8% NaCl and 29.4% fat) thetized with isofurane. Te thoracic aorta was rapidly [HD-vehicle] Vehicle removed, gently cleaned taking care not to damage the endothelium, and it was cut into 3-mm rings. Te rings [HD-pitavastan] Pitavastan (0.3 mg/kg) were then cut open. Open aortic rings were placed in [HD-pemafibrate] Pemafibrate (0.5 mg/kg) a 10-mL organ bath containing Krebs–Henseleit solu- [HD-combinaon] Pitavastan + pemafibrate tion (KHS; in mmol/L: 118 NaCl, 4.7 KCl, 2.5 CaCl 2, 1.2 Age (weeks) 7 19 KH2PO4, 1.2 MgSO 4, 25 NaHCO 3, 11.1 glucose).
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