title: LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice.
abstract: Angiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin-induced diabetic mice.
  
  
  
  Male C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-β (TGF-β) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group.
  
  
  
  The ARNi LCZ696 improved cardiac function with the reduction of fibrosis in an HF-rEF model in diabetic mice, by suppressing TGF-β. This effect may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696.
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Suematsu
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.|Department of Molecular Cardiovascular Therapeutics, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Miura
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Goto
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Yoshino
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Arimura
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwano
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwata
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yahiro
authors.affiliation: Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.|Department of Molecular Cardiovascular Therapeutics, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Saku
mesh_terms: D000613:Aminobutyrates / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics; D001713:Biphenyl Compounds; D003921:Diabetes Mellitus, Experimental; D004338:Drug Combinations; D005355:Fibrosis; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013318:Stroke Volume; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D012333:RNA, Messenger; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000068756:Valsartan; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Cardiac function; Diabetes mellitus; Fibrosis; Heart failure with reduced ejection fraction; LCZ696