TY - JOUR
T1 - Anti-atherogenic effects of the combination therapy with olmesartan and azelnidipine in diabetic apolipoprotein E-deficient mice
AU - Noda, Kazuki
AU - Hosoya, Maki
AU - Nakajima, Sota
AU - Ohashi, Junko
AU - Fukumoto, Yoshihiro
AU - Shimokawa, Hiroaki
PY - 2012
Y1 - 2012
N2 - Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE-/-) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE-/- mice. Diabetic ApoE-/- mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/ kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE-/- mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.
AB - Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE-/-) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE-/- mice. Diabetic ApoE-/- mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/ kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE-/- mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.
KW - Angiotensin II receptor blocker
KW - Atherosclerosis
KW - Calcium channel blocker
KW - Combination therapy
KW - Oxidative stress
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U2 - 10.1620/tjem.228.305
DO - 10.1620/tjem.228.305
M3 - Article
C2 - 23124103
AN - SCOPUS:84869052334
VL - 228
SP - 305
EP - 315
JO - Tohoku Journal of Experimental Medicine
JF - Tohoku Journal of Experimental Medicine
SN - 0040-8727
IS - 4
ER -