Objective. We used high-resolution peripheral vascular ultrasound imaging to assess endothelial function in hyperuricaemic patients. Methods. Hyperuricaemia was defined as a serum uric acid concentration of >7.7 mg/dl in men or >6.6 mg/dl in women. Measurements of endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation were performed in 46 hyperuricaemic patients and an equal number of healthy age- and gender-matched normal controls by high-resolution two-dimensional ultrasonographic imaging of the brachial artery. The serum levels of glucose, creatinine, alanine aminotransferase (ALT), lipid profiles and high-sensitivity CRP were measured for both the study groups. Results. The serum uric acid levels averaged 9.24 (1.16) and 6.18 (0.99) mg/dl in the hyperuricaemic and control groups, respectively. Body weight and BMI were significantly higher in the hyperuricaemic group than in the control group. The serum levels of creatinine, ALT, triglyceride and high-sensitivity CRP were significantly different between the two groups. The FMD values were significantly lower in the hyperuricaemic patients than in the controls [4.45% (3.13%) vs 7.10% (2.48%); P < 0.001]. The FMD values were negatively associated with serum uric acid levels (r =0.273; P = 0.009). Multivariate regression analysis showed that the presence of hyperuricaemia (� =0.384; P < 0.001) and body weight (� = 0.215; P = 0.017) were independent determinants of low FMD values.

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Association between endothelial dysfunction and hyperuricaemia

Aims Endothelial dysfunction is an initial and vascular smooth muscle cell (VSMC) apoptosis, a later step of atherosclerosis. Hypothyroidism accelerates atherosclerosis. However, the early events responsible for this pro-atherosclerotic effect are unclear.

Methods and results Rats were resistant to induction of atherosclerosis by high cholesterol diet alone, but became susceptible in hypothyroid state achieved by administration of propylthiouracil (PTU) for 6 weeks. VSMC dysfunction and apoptosis were obvious within 1 week after PTU treatment, without signs of endothelial dysfunction. This early VSMC damage was caused by hypothyroidism but not the high cholesterol diet. In ApoE knockout mice, PTU-induced hypothyroidism triggered early VSMC apoptosis, increased oxidative stress, and accelerated atherosclerosis development. Thyroid hormone supplementation (T4, 10, or 50 μg/kg) prevented atherogenic phenotypes in hypothyroid rats and mice. In rats, thyroidectomy caused severe hypothyroidism 5 days after operation, which also led to rapid VSMC dysfunction and apoptosis. In vitro studies did not show a direct toxic effect of PTU on VSMCs. In contrast, thyroid hormone (T3, 0.75 μg/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRα1, rather than TRβ1 and TRβ2 receptors. TRα1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone.

Conclusion These findings provide an in vivo example for VSMC apoptosis as an early trigger of hypothyroidism-associated atherosclerosis, and reveal activation of TRα1 receptors to prevent VSMC apoptosis as a therapeutic strategy in this disease.

Vascular smooth muscle cell apoptosis is an early trigger for hypothyroid atherosclerosis

Aims Caloric restriction (CR) and female gender attenuate oxidative damage and improve vascular endothelium-dependent relaxation (EDR). Multiple mechanisms that ameliorate vascular O2•− could enhance the NO•/O2•− balance and thus improve EDR. The aim of this study is to compare the effects of short-term (2 weeks) CR and gender on molecular mechanisms involved in NO•/O2•− balance and EDR.

Methods and results Wistar rats (8 weeks old) of both genders were fed ad libitum (control) or were subjected to CR (60% of food intake of controls) for 2 weeks. Plasma levels of NO•, insulin, and ghrelin, EDR, vascular NO• and O2•− production, as well as endothelial NO• synthase (eNOS) and NADPH oxidase (Nox) expression were examined and analysed. CR improved EDR and vascular NO• levels and ameliorated NADPH-sensitive O2•− production in male rats more than in females. Both CR and female gender reduced mRNA expression of Nox1 and Nox p22phox (p22phox); however, CR reduced Nox4 and p47phox only in males. Protein expression studies showed that CR enhanced eNOS and reduced Nox4 only in males.

Conclusion Short-term CR improved the NO•/O2•− balance by lowering vascular O2•− production through decreased expression of Nox in males, thus enhancing bioactive NO• levels and EDR. In this regard, CR shifted the state of vascular NO•/O2•− balance in males to a state similar to that in females.

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Gender-specific effects of caloric restriction on the balance of vascular nitric oxide and superoxide radical

Background: Propylthiouracil (PTU) enhances nitric oxide production and inhibits smooth muscle cell proliferation, suggesting a possible role in the prevention of pulmonary arterial hypertension (PAH). Methods and Results: The 30 male Sprague-Dawley rats were randomized to receive saline injection only (group 1), monocrotaline (MCT) (70 mg/kg) only (group 2) or MCT + 0.1% PTU in drinking water (group 3) given on day 5 after MCT administration. By day 35, western blot showed lower connexin43 (Cx43) and membranous protein kinase C-e expressions in the right ventricle (RV) of group 2 animals than in the other groups (all P<0.05). Conversely, Cx43 expression in the lung was higher in group 2 than in other groups (all P<0.02). Additionally, mRNA expressions of matrix metalloproteinase-9, tissue necrotic factor-α, and caspase-3 were higher, whereas Bcl-2 and endothelial nitric oxide synthase were lower, in the lungs and RV of group 2 rats than in the other groups (all P<0.05). Moreover, the numbers of alveolar sacs and lung arterioles were also reduced in group 2 than in other groups (all P<0.05), and RV systolic pressure and RV weight were increased in group 2 compared with other groups (all P<0.001). Conclusions: PTU effectively attenuates complications associated with MCT-induced PAH. (Circ J 2009; 73: 1722-1730)

Shih-Hsuan Chou

Papers

Propylthiouracil, independent of its antithyroid effect, produces endothelium-dependent vasodilatation through induction of nitric oxide bioactivity.