Effects of pravastatin on progression of glucose intolerance and cardiovascular remodeling in a type II diabetes model

J Am Coll Cardiol. 2004 Aug 18;44(4):904-13. doi: 10.1016/j.jacc.2004.04.050.


Objectives: We examined the effects of early treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on the progression of glucose intolerance and cardiovascular remodeling in a model of spontaneously developing type II diabetes mellitus (DM), the Otsuka Long-Evans Tokushima Fatty (OLETF) rats.

Background: Clinical trials showed that pravastatin prevented new-onset DM in hypercholesterolemic patients, and that it was effective in prevention of cardiovascular events in diabetics.

Methods: The OLETF rats were treated with pravastatin (100 mg/kg/day) from 5 weeks of age and compared with age-matched untreated OLETF rats and normal Long-Evans Tokushima Otsuka (LETO) rats on serial oral glucose tolerance tests (OGTT) and Doppler echocardiography and on histopathological/biochemical analyses of the heart at 30 weeks.

Results: The OGTT revealed that 40% and 89% of untreated OLETF rats were diabetic at 20 and 30 weeks, respectively, but 0% and only 30%, respectively, were diabetic in the treated OLETF. Left ventricular diastolic function was found impaired from 20 weeks in untreated OLETF but remained normal in the treated-OLETF. The wall-to-lumen ratio and perivascular fibrosis of coronary arteries were increased in untreated-OLETF but were limited in the treated-OLETF at 30 weeks. Moreover, cardiac expressions of a fibrogenic growth factor, transforming growth factor-beta1 (TGF-beta1), and a proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1), were increased in untreated-OLETF. However, in the treated-OLETF, overexpressions of TGF-beta1 and MCP-1 were attenuated, which was associated with overexpression of endothelial nitric oxide synthase (eNOS) (2.5-fold of control LETO).

Conclusions: Early pravastatin treatment prevented cardiovascular remodeling in the spontaneous DM model by retarding the progression of glucose intolerance, overexpressing cardiac eNOS, and inhibiting overexpressions of fibrogenic/proinflammatory cytokines.

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Cholesterol / blood
  • DNA Primers
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Disease Models, Animal
  • Glucose Tolerance Test
  • Hydroxymethylglutaryl CoA Reductases / administration & dosage
  • Hydroxymethylglutaryl CoA Reductases / therapeutic use*
  • Immunohistochemistry
  • Insulin / blood
  • Leptin / blood
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type III
  • Pravastatin / administration & dosage
  • Pravastatin / therapeutic use*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Inbred OLETF
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Triglycerides / blood
  • Tumor Necrosis Factor-alpha
  • Ventricular Remodeling / drug effects*


  • Blood Glucose
  • Chemokine CCL2
  • DNA Primers
  • Insulin
  • Leptin
  • RNA, Messenger
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Triglycerides
  • Tumor Necrosis Factor-alpha
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Pravastatin