Inhibition of Atherosclerosis Progression, Intimal Hyperplasia, and Oxidative Stress by Simvastatin and Ivabradine May Reduce Thoracic Aorta's Stiffness in Hypercholesterolemic Rabbits

J Cardiovasc Pharmacol Ther. 2016 Jul;21(4):412-22. doi: 10.1177/1074248415617289. Epub 2015 Nov 25.

Abstract

Aims: This study aims to evaluate atherosclerosis, oxidative stress, and arterial stiffness attenuation by simvastatin and ivabradine in hyperlipidemic rabbits.

Methods and results: Forty rabbits were randomly divided into 4 groups: atherogenic diet (group C), atherogenic diet plus simvastatin (group S), atherogenic diet plus ivabradine (group I), and atherogenic diet plus simvastatin and ivabradine (group S + I). After 9 weeks, rabbits were euthanized and descending aortas excised for mechanical testing. Atherogenic diet induced the development of significant atherosclerotic lesions in group C animals but in none of groups S, I, and S + I. RAM-11 and HHF-35-positive cells were significantly reduced in groups S, I, and S + I compared with group C (P < .001). A significant neointimal hyperplasia and intima-media ratio reduction was demonstrated in groups S (P = .015 and P < .001), I (P = .021 and P < .001), and S + I (P = .019 and P < .001) compared with group C. Protein nitrotyrosine levels were significantly decreased in group S compared with group C (P = .009), and reactive oxygen species levels were decreased in group I compared with group C (P = .011). Aortic stiffness was significantly reduced in groups S, I, and S + I compared with group C (P = .003, P = .011, and P = .029).

Conclusion: Simvastatin and ivabradine significantly inhibited intimal hyperplasia and oxidative stress contributing to aortic stiffness reduction in hyperlipidemic rabbits.

Keywords: arterial stiffness; atherosclerosis; ivabradine; oxidative stress; simvastatin.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Aorta, Thoracic / drug effects*
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Aorta, Thoracic / physiopathology
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / physiopathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology
  • Atherosclerosis / prevention & control*
  • Benzazepines / pharmacology*
  • Diet, Atherogenic
  • Disease Models, Animal
  • Disease Progression
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / metabolism
  • Hypercholesterolemia / pathology
  • Hypercholesterolemia / physiopathology
  • Hyperplasia
  • Ivabradine
  • Male
  • Neointima*
  • Oxidative Stress / drug effects*
  • Plaque, Atherosclerotic
  • Rabbits
  • Simvastatin / pharmacology*
  • Vascular Stiffness / drug effects*

Substances

  • Antioxidants
  • Benzazepines
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Ivabradine
  • Simvastatin