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

Yang Yu, MD, PhD^*, Koji Ohmori, MD, PhD^*,*, Yan Chen, MD^*, Chubun Sato, PhD, Hideyasu Kiyomoto, MD, PhD^*, Kaori Shinomiya, MD, PhD^*, Hiroto Takeuchi, MD, PhD^*, Katsufumi Mizushige, MD, PhD, FACC^* and Masakazu Kohno, MD, PhD^*

^* Second Department of Internal Medicine
Department of Molecular Biology, Kagawa University School of Medicine, Kagawa, Japan

Manuscript received December 26, 2003; revised manuscript received March 11, 2004, accepted April 13, 2004.

^* Reprint requests and correspondence: Dr. Koji Ohmori, Second Department of Internal Medicine, Kagawa University School of Medicine, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan (Email: komori{at}med.kagawa-u.ac.jp).

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-ß1 (TGF-ß1), and a proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1), were increased in untreated-OLETF. However, in the treated-OLETF, overexpressions of TGF-ß1 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.

Abbreviations and Acronyms   DM = diabetes mellitus   DT = deceleration time of early diastolic left ventricular inflow   E/A = early-to-late diastolic left ventricular inflow velocity ratio   eNOS = endothelial nitric oxide synthase   GAPDH = glyceraldehyde 3-phosphate dehydrogenase   LETO = Long-Evans Tokushima Otsuka   LV = left ventricular/ventricle   MCP = monocyte chemoattractant protein   mRNA = messenger ribonucleic acid   NO = nitric oxide   OGTT = oral glucose tolerance test   OLETF = Otsuka Long-Evans Tokushima Fatty   TGF = transforming growth factor   TNF = tumor necrosis factor   RT-PCR = reverse transcription-polymerase chain reaction

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