Published Online
on June 20, 2005

A more recent version of this article appeared on August 1, 2005

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Submitted on October 26, 2004
Revised on November 16, 2004

Pioglitazone Improves Aortic Wall Elasticity in a Rat Model of Elastocalcinotic Arteriosclerosis

Virginie Gaillard; Daniel Casellas; Carole Seguin-Devaux; Hervé Schohn; Michel Dauça; Jeffrey Atkinson^*; and Isabelle Lartaud

From the Unité Mixte UHP-INSERM U684, Pharmacology Laboratory Faculté de Pharmacie (V.G., J.A., I.L.), and Faculté de Médecine (C.S.-D.), Université Henri Poincaré Nancy-1, Nancy; Groupe Rein et Hypertension (EA3127) (D.C.), Institut Universitaire de Recherche Clinique, Montpellier; Peroxisome Proliferators (EA 3446) (H.S., M.D.), Faculté des Sciences et Techniques, Université Henri Poincaré Nancy-1, Nancy, France.

^* To whom correspondence should be addressed. E-mail: Jeffrey.Atkinson{at}pharma.uhp-nancy.fr.

Abstract--Specific treatment of age-related aortic wall arteriosclerosis and stiffening is lacking. Because ligands for peroxisome proliferator-activated receptor have beneficial effects on the arterial wall in atherosclerosis, via an antiinflammatory mechanism, we investigated whether long-term pioglitazone (Pio) treatment protects against another form of vascular wall disease, arteriosclerosis. We evaluated, in a rat model of elastocalcinotic arteriosclerosis (hypervitaminosis D and nicotine [VDN]), whether Pio (3 mg · kg^-1 per day for 1.5 month PO) attenuated arteriosclerosis and its consequences: aortic wall rigidity, increased aortic pulse pressure, and left ventricular hypertrophy. In VDN rats, medial calcification was associated with monocyte/macrophage infiltration and induction of tumor necrosis factor and interleukin 1. Pio increased nuclear peroxisome proliferator-activated receptor immunostaining in the aortic wall, decreased tumor necrosis factor (P<0.05 versus VDN Pio^-), tended to decrease interleukin 1 mRNA expression (P=0.08 versus VDN Pio^-), blunted aortic wall calcification (271±69, P<0.05 versus VDN Pio^- 562±87 µmol · g^-1 dry weight) and prevented fragmentation of elastic fibers (segments per 10 000 µm²: 8.4±0.3; P<0.05 versus VDN Pio^- 10.5±0.6). Pio reduced aortic wall stiffness (elastic modulus/wall stress: 4.8±0.6; P<0.05 versus VDN Pio^- 10.0±1.6), aortic pulse pressure (30±2 mm Hg; P<0.05 versus VDN Pio^- 39±4) and left ventricular hypertrophy (1.58±0.05 g · kg^-1; P<0.05 versus VDN Pio^- 1.76±0.06). In conclusion, long-term Pio treatment attenuates aortic wall elastocalcinosis and, thus, lowers aortic wall stiffness, aortic pulse pressure, and left ventricular hypertrophy.

Key words: extracellular matrix • peroxisome proliferator-activated receptor • arteriosclerosis • calcium • pulse pressure

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