Reciprocal regulation of cholesterol excretion in apolipoprotein E-null mice by angiotensin II type 1 and type 2 receptor deficiency.

AIMS: The effects of AT(1) and AT(2) receptor deficiency on the intake and excretion of cholesterol were examined using atherosclerotic apolipoprotein E-null (ApoEKO) mice. MAIN METHODS: ApoEKO, AT(1)a/ApoEKO and AT(2)/ApoEKO mice received a high-cholesterol diet (HCD: 1.25% cholesterol) for 10 days before sampling. KEY FINDINGS: Plasma total cholesterol level was lower in AT(1)a/ApoEKO mice and higher in AT(2)/ApoEKO mice than in ApoEKO mice with a high cholesterol intake. In these mice, cholesterol content in feces was higher in AT(1)a/ApoEKO mice and lower in AT(2)/ApoEKO mice than in ApoEKO mice. Moreover, cholesterol content in bile tended to be higher in AT(1)a/ApoEKO mice and lower in AT(2)/ApoEKO mice than in ApoEKO mice, while a significant difference was observed only between AT(1)a/ApoEKO and AT(2)/ApoEKO mice. Cholesterol content and expression of HMG-CoA reductase and LDL receptor in liver were not different among the groups. Similar but weaker changes were also observed with a normal standard diet. Treatment with an AT(1) receptor blocker, irbesartan, increased cholesterol content in bile and tended to increase cholesterol excretion into feces in ApoEKO mice with HCD. SIGNIFICANCE: These results suggest that AT(1) and AT(2) receptor stimulation was involved in the regulation of cholesterol excretion into bile and feces, and that the regulation acted reciprocally in a cholesterol overload condition with HCD.

Possible involvement of AT2 receptor dysfunction in age-related gender difference in vascular remodeling.

This study explored the possible involvement of AT(2) receptor stimulation in the age-related gender difference in vascular remodeling of mouse femoral artery induced by cuff placement. In the young adult group of wild-type mice (10 weeks of age), the increase in DNA synthesis, neointimal formation, expression of chemokines, and superoxide anion production in the injured femoral artery were smaller in female than in male mice. These gender differences were smaller in the aged group (50-55 weeks of age) of wild-type mice, because vascular responses of female mice in the aged group were stronger than those in the young group. Treatment with 17ß-estradiol attenuated vascular remodeling in aged female mice. AT(2) receptor expression in the injured artery was higher in female than in male in the young group. AT(2) receptor expression in the injured artery of female mice was lower in the aged group than in the young group. Lack of AT(2) receptor increased neointimal formation in the aged group and reduced the inhibitory action of 17ß-estradiol in aged female mice. Our findings suggest a possibility that the change in AT(2) receptor stimulation by aging might be involved in the response to estrogen and improvement of vascular remodeling in the aged female group.

Nifedipine, a calcium-channel blocker, attenuated glucose intolerance and white adipose tissue dysfunction in type 2 diabetic KK-A(y) mice.

BACKGROUND: To explore the metabolic actions of nifedipine on diabetes, we examined glucose intolerance and white adipose tissue changes in type 2 diabetic KK-A(y) mice. METHODS: Male KK-A(y) mice were treated with nifedipine (1.5 mg/kg/day in lab chow) for 5 weeks, which did not affect blood pressure or feeding of KK-A(y) mice. RESULTS: After treatment with nifedipine, body weight tended to decrease and the weight of white adipose tissue was reduced. Without food restriction, nifedipine decreased plasma insulin level, while plasma glucose level tended to decrease. In oral glucose tolerance test, nifedipine suppressed the increase in glucose level after a glucose load without affecting plasma insulin concentration. Nifedipine also improved the result of insulin tolerance test. In white adipose tissue, nifedipine increased adipocyte number and the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and adipocyte fatty acid-binding protein related to adipocyte differentiation. In addition, expression of adiponectin, insulin receptor, insulin receptor substrate-1, and glucose transporter type-4 was also increased by nifedipine. Nifedipine also increased the expression of NO synthase in white adipose tissue. Nifedipine did not affect expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors in white adipose tissue. Such changes in white adipose tissue were apparent in retroperitoneal adipose tissue. Nifedipine did not change the expression of angiotensin receptors, renin receptor, and angiotensinogen in white adipose tissue. Moreover, nifedipine attenuated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and increased superoxide dismutase (SOD) activity in white adipose tissue. CONCLUSION: These results suggest that nifedipine can enhance insulin sensitivity and reduce white adipose tissue, possibly related to stimulation of adipocyte differentiation.

Improvement of glucose intolerance by combination of pravastatin and olmesartan in type II diabetic KK-A(y) mice.

The effects of the coadministration of pravastatin and an angiotensin type 1 (AT(1)) receptor blocker, olmesartan, on glucose intolerance were examined using type II diabetic mice. Male KK-A(y) mice (8 weeks of age) were treated with pravastatin and/or olmesartan for 2 weeks. An oral glucose tolerance test (OGTT) was performed with an administration of 2 g kg(-1) glucose. Tissue glucose uptake was determined using 2-[(3)H]deoxyglucose. The treatment of mice with pravastatin attenuated the increase in the plasma glucose level during OGTT in a dose-dependent manner, without affecting the plasma insulin level. Pravastatin increased glucose uptake in insulin-sensitive tissue such as the skeletal muscle and adipose tissue after treatment at 5-20 mg kg(-1) day(-1) for 2 weeks, but not at 1 mg kg(-1) day(-1). The combination of a noneffective dose of pravastatin (1 mg kg(-1) day(-1)) and a noneffective dose of olmesartan (0.5 mg kg(-1) day(-1)) synergistically improved OGTT without affecting the plasma insulin level. This combination also increased 2-[(3)H]deoxyglucose uptake in the skeletal muscle and adipose tissue. The effects of pravastatin or olmesartan on OGTT and tissue 2-[(3)H]deoxyglucose uptake were significantly enhanced by an antioxidant, tempol, whereas the effects of a pravastatin-olmesartan combination were not further enhanced by tempol. These results indicate that the combination of pravastatin and olmesartan synergistically improves glucose intolerance through an increase in tissue glucose uptake. The effects seem to be mediated by an increase in insulin sensitivity through the inhibition of oxidative stress.