DPP-4 inhibitor induces FGF21 expression via sirtuin 1 signaling and improves myocardial energy metabolism
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ORIGINAL ARTICLE
DPP‑4 inhibitor induces FGF21 expression via sirtuin 1 signaling and improves myocardial energy metabolism Nozomi Furukawa1,2 · Norimichi Koitabashi1 · Hiroki Matsui2 · Hiroaki Sunaga1 · Yogi Umbarawan1 · Mas Rizky A. A. Syamsunarno1 · Aiko Yamaguchi3 · Masaru Obokata1 · Hirofumi Hanaoka3 · Tomoyuki Yokoyama2 · Masahiko Kurabayashi1 Received: 28 May 2020 / Accepted: 2 October 2020 © The Author(s) 2020
Abstract Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used incretin-based therapy for the treatment of type 2 diabetes. We investigated the cardioprotective effect of a DPP-4 inhibitor, vildagliptin (vilda), on myocardial metabolism and cardiac performance under pressure overload. Mice were treated with either vehicle or vilda, followed by transverse aortic constriction (TAC). After 3 weeks of TAC, cardiac hypertrophy and impairment of systolic function were attenuated in vilda-treated mice. Pressure–volume analysis showed that vilda treatment significantly improved left-ventricular contractile efficiency in TAC heart. Myocardial energy substrate analysis showed that vilda treatment significantly increased glucose uptake as well as fatty acid uptake. Fibroblast growth factor 21 (FGF21), a peptide involved in the regulation of energy metabolism, increased in TAC heart and was further increased by vilda treatment. FGF21 was strongly expressed in cardiac fibroblasts than in cardiomyocytes in mouse heart after TAC with vilda treatment. Vilda treatment markedly induced FGF21 expression in human cardiac fibroblasts through a sirtuin (Sirt) 1-mediated pathway, suggesting that fibroblast-mediated FGF21 expression may regulate energy metabolism and exert vilda-mediated beneficial effects in stressed heart. Vilda induced a metabolic regulator, FGF21 expression in cardiac fibroblasts via Sirt1, and increased contractile efficiency in murine pressure-overloaded heart. Keywords Heart failure · Hypertrophy · Metabolism · Cardiac fibroblast
Introduction Heart failure (HF) is caused by various heart diseases including cardiomyopathy, hypertensive heart disease, valvular disease, and ischemic heart disease. Chronic HF is commonly related to lifestyle diseases like obesity, hypertension, dyslipidemia, and diabetes mellitus [1–3]. In the Framingham Heart Study, the risk of heart failure in patients * Norimichi Koitabashi [email protected] 1
Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3‑39‑22, Showa‑machi, Maebashi, Gunma 371‑8511, Japan
2
Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Maebashi, Gunma, Japan
3
Department of Bioimaging Information Analysis, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
with diabetes was increased twofold in males and fivefold in females compared to patients without diabetes [4]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral hypoglycemics that block the enzyme DPP-4. DPP-4 is a serine protease, which is expressed in many cells and tiss
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