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

Specific treatment of age-related aortic wall arteriosclerosis and stiffening is lacking. Because ligands for peroxisome proliferator-activated receptor gamma 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 alpha and interleukin 1beta. Pio increased nuclear peroxisome proliferator-activated receptor gamma immunostaining in the aortic wall, decreased tumor necrosis factor alpha (P <0.05 versus VDN Pio-), tended to decrease interleukin 1beta mRNA expression (P =0.08 versus VDN Pio-), blunted aortic wall calcification (271+/-69, P <0.05 versus VDN Pio- 562+/-87 micromol . g(-1) dry weight) and prevented fragmentation of elastic fibers (segments per 10,000 microm2: 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.