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

Eur J Heart Fail. 2016 Apr;18(4):386-93. doi: 10.1002/ejhf.474. Epub 2016 Jan 7.


Aims: 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.

Methods and results: 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.

Conclusion: 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.

Keywords: Cardiac function; Diabetes mellitus; Fibrosis; Heart failure with reduced ejection fraction; LCZ696.

MeSH terms

  • Aminobutyrates / pharmacology*
  • Angiotensin Receptor Antagonists / pharmacology*
  • Animals
  • Atrial Natriuretic Factor / drug effects
  • Atrial Natriuretic Factor / genetics
  • Biphenyl Compounds
  • Diabetes Mellitus, Experimental*
  • Drug Combinations
  • Fibrosis
  • Heart / drug effects*
  • Heart / physiopathology
  • Heart Failure / pathology
  • Heart Failure / physiopathology*
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Heart Ventricles / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / physiopathology*
  • Myocardium / pathology*
  • Neprilysin / antagonists & inhibitors*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Stroke Volume
  • Tetrazoles / pharmacology*
  • Transforming Growth Factor beta / drug effects
  • Transforming Growth Factor beta / genetics
  • Valsartan


  • Aminobutyrates
  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Drug Combinations
  • RNA, Messenger
  • Tetrazoles
  • Transforming Growth Factor beta
  • Valsartan
  • Atrial Natriuretic Factor
  • Neprilysin
  • sacubitril and valsartan sodium hydrate drug combination