Anti-atherosclerotic Effects Of Pioglitazone In ApoE^-/- Mice

Background:Atherosclerotic diseases, especially coronary heart disease and cerebral vascular disease, are a serious health epidemic in the world. Although the principal clinical complications of atherosclerosis, such as myocardial infarction and stroke, usually occur in middle-aged or older people, the atherogenic process actually begins in childhood and early adult life, with a preclinical phase lasting many decades. This pattern provides a window of opportunity for the presymptomatic detection of the disease, the identification of high-risk subjects, and the application of appropriate preventive strategies. Potential roles of adiponectin and its receptors in the pathogenesis of atherosclerosis has been studied intensively in recent years. Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue. Many studies revealed plasma adiponectin level is significantly reduced in patients with hypertension, insulin resistance, type 2 diabetes mellitus and obesity. Moreover, low plasma adiponectin level has now been considered as an independent risk factor for coronary heart disease. There are two distinct adiponectin receptors AdipoR1 and AdipoR2 cloned in 2003, with similar structure but different tissue distribution. AdipoR1 is ubiquitously expressed but most abundantly in skeletal muscle, whereas AdipoR2 is most abundantly expressed in liver. Thiazolidinedione (TZD) is an new type of insulin sensitizers . It was reported that TZDs can inhibit atherosclerosis of carotid in type 2 diabetes mellitus. However whether adiponectin and its receptors play any roles in the anti-atherosclerotic effects of TZDs are still largely unknown. Aim:To study the effects of Pioglitazone on atherosclerosis in ApoE-/- mice,and to investigate the involvement of adiponectin and its receptors in the anti-atherosclerosis effects of TZDs.Methods: ApoE-/- mice (17 weeks aged, male )were fed with high-fat chow for the induction of atherosclerosis and were divided into three subgroups: placebo(n=10), low-dose(10mg/kg/d) pioglitazone therapy(n=10), and high-dose(20mg/kg/d) pioglitazone therapy(n=11). Same aged wild type C57BL/6J mice(n=9) were used as control. Aortic atherosclerosis and intima-media thickness (IMT) of abdominal aorta were monitored, and plasma adiponectin was also measured. Expression levels of the adiponectin receptors (AdipoR1 and AdipoR2) in vessels were analyzed(RT-PCR).Results: (1), Aortic atherosclerotic lesions were observed in ApoE-/- mice but not in wild type mice. Interestingly, these lesions were significantly prevented by high-dose pioglitazone therapy. Consistently, ApoE-/- mice had increased IMT of abdominal aorta that was significantly reversed by high-dose pioglitazone therapy (p<0.05). (2), The level of plasma adiponectin was significantly lower in ApoE-/- mice (P<0.05), which could be increased by low- and high-dose pioglitazone therapy (p<0.05). (3), ApoE-/- mice had reduced AdipoR1 mRNA level and reduced ratio of AdipoR1/AdipoR2 (p<0.05); high dose pioglitazone therapy could upregulate AdipoR1 mRNA expression (p>0.05) and increase the ratio of AdipoR1/AdipoR2 (p<0.01).Conclusions : Atherosclerosi of ApoE-/- mice is correlated with reduced plasm adiponectin and reduced expression of AdipoR1 in vascular tissue; Pioglitazone inhibits aortic atherosclerosis in ApoE-/- mice, and these effects are correlated with increased plasma adiponectin level and the expression of AdipoR1 m-RNA in vessels.