The long-term effect of angiotensin II type 1a receptor deficiency on hypercholesterolemia-induced atherosclerosis.
Angiotensin II type 1 receptor may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. In the present study, we investigated the long-term effect of angiotensin II type 1a receptor (AT1a) deficiency on hypercholesterolemia-induced atherosclerosis by the use of AT1a-knockout (AT1a-KO) mice and apolipoprotein E-knockout (apoE-KO) mice. AT1a-KO were crossed with apoE-KO, generating double-knockout (D-KO) mice. Mice were fed a standard diet and analyzed at 25- or 60-weeks-old. The quantification of atherosclerotic volume in the aortic root revealed that the atherosclerotic lesions of D-KO mice were significantly smaller than those of apoE-KO mice at 25-week-old (0.81+/-0.16 mm2 vs. 1.05+/-0.21 mm2, p<0.001) and at 60-week-old (0.89+/-0.11 mm2 vs. 2.44+/-0.28 mm2, p<0.001). Surprisingly, there was no significant difference in atherosclerotic lesion size of D-KO mice at 25- and 60-week-old, suggesting that AT1a deficiency completely protected against the age-related progression of atherosclerosis. The amounts of collagen and elastin, the expression of p22phox, serum amyloid P (SAP), matrix metalloproteinase (MMP)-2, and MMP-9, and the number of apoptotic cells of D-KO mice were lower than those of apoE-KO mice. Furthermore, we confirmed that the expression of procollagen alpha1(I), procollagen alpha1(III), tropoelastin, p22phox, SAP, MMP-2, and MMP-9 decreased in cultured vascular smooth muscle cells from D-KO mice compared with those of apoE-KO mice. In conclusion, AT1a deficiency reduces atherosclerotic lesion size of apoE-KO mice and protects against the age-related progression of atherosclerosis. Reduction of oxidative stress, apoptosis, and MMP expression in atherosclerotic lesions by AT1a deficiency may contribute to plaque size.
Eto
Hideyuki
H
Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan.
Miyata
Masaaki
M
Shirasawa
Takahiro
T
Akasaki
Yuichi
Y
Hamada
Narisato
N
Nagaki
Aya
A
Orihara
Koji
K
Biro
Sadatoshi
S
Tei
Chuwa
C
D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000235:genetics*; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D001794:Blood Pressure; D001835:Body Weight; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D005109:Extracellular Matrix / Q000378:metabolism; D006339:Heart Rate; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*
D001057:Apolipoproteins E; D044140:Receptor, Angiotensin, Type 1; C075750:8-epi-prostaglandin F2alpha; D002784:Cholesterol; D015237:Dinoprost