Protective effects of low-dose rosuvastatin on isoproterenol-induced chronic heart failure in rats by regulation of DDAH-ADMA-NO pathway

Cardiovasc Ther. 2017 Apr;35(2). doi: 10.1111/1755-5922.12241.


Aims: Cardiovascular disease is the leading cause of death with high morbidity and mortality, and chronic heart failure is the terminal phase of it. This study aimed to investigate the protective effects of the low-dose rosuvastatin on isoproterenol-induced chronic heart failure and to explore the possible related mechanisms.

Methods: Male Sprague Dawley rats were given isoproterenol 5 mg/kg once a day for 7 days to establish heart failure model by subcutaneous injection. Simultaneously, low-dose rosuvastatin (5 mg/kg) was orally administrated from day 1 to day 14. Protective effects were evaluated by hemodynamic parameter, histopathological variables, serum asymmetric dimethylarginine (ADMA), cardiac troponin I (cTnI), brain natriuretic peptide (BNP) and myocardial nitric oxide (NO), and the levels of dimethylarginine dimethylaminohydrolase 2 (DDAH2), arginine methyltransferases 1 (PRMT1) and endothelial nitric oxide synthase (eNOS) expression were analyzed.

Results: Therapeutic rosuvastatin (5 mg/kg) significantly attenuated isoproterenol-induced hypertrophy, remodeling and dysfunction of ventricle, reduced the increased serum content of ADMA, cTnI, and BNP, and elevated myocardial NO in rats (P<.05). Besides, rosuvastatin also significantly inhibited fibrosis of myocardium, normalized the increased PRMT1 and decreased DDAH2 expression.

Conclusions: Low-dose rosuvastatin exerted cardioprotective effects on isoproterenol-induced heart failure in rats by modulating DDAH-ADMA-NO pathway, and it may present the new therapeutic value in ameliorating chronic heart failure.

Keywords: ADMA; DDAH; NO; Chronic heart failure; Isoproterenol; Rosuvastatin.

MeSH terms

  • Amidohydrolases / metabolism*
  • Animals
  • Biomarkers / blood
  • Cardiotonic Agents / pharmacology*
  • Disease Models, Animal
  • Fibrosis
  • Heart Failure / chemically induced
  • Heart Failure / enzymology
  • Heart Failure / physiopathology
  • Heart Failure / prevention & control*
  • Hypertrophy, Left Ventricular / chemically induced
  • Hypertrophy, Left Ventricular / enzymology
  • Hypertrophy, Left Ventricular / physiopathology
  • Hypertrophy, Left Ventricular / prevention & control
  • Isoproterenol*
  • Male
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Natriuretic Peptide, Brain / blood
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type III / metabolism
  • Protein-Arginine N-Methyltransferases / metabolism
  • Rats, Sprague-Dawley
  • Rosuvastatin Calcium / pharmacology*
  • Troponin I / blood
  • Ventricular Dysfunction, Left / chemically induced
  • Ventricular Dysfunction, Left / enzymology
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control
  • Ventricular Function, Left / drug effects
  • Ventricular Pressure / drug effects
  • Ventricular Remodeling / drug effects


  • Biomarkers
  • Cardiotonic Agents
  • Troponin I
  • Natriuretic Peptide, Brain
  • Nitric Oxide
  • Rosuvastatin Calcium
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • PRMT1 protein, rat
  • Protein-Arginine N-Methyltransferases
  • Amidohydrolases
  • dimethylargininase
  • Isoproterenol