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Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice.
Circulation. 2005 Sep 13; 112(11):1636-43.Circ

Abstract

BACKGROUND

The role of angiotensin II (Ang II) type 2 (AT2) receptor in atherosclerosis was explored with the use of AT2 receptor/apolipoprotein E (ApoE)-double-knockout (AT2/ApoE-DKO) mice, with a focus on oxidative stress.

METHODS AND RESULTS

After treatment with a high-cholesterol diet (1.25% cholesterol) for 10 weeks, ApoE-knockout (KO) mice developed atherosclerotic lesions in the aorta. In AT2/ApoE-DKO mice receiving a high-cholesterol diet, the atherosclerotic changes were further exaggerated, without significant changes in plasma cholesterol level and blood pressure. In the atherosclerotic lesion, an increase in superoxide production, NADPH oxidase activity, and expression of p47phox was observed. These changes were also greater in AT2/ApoE-DKO mice. An Ang II type 1 (AT1) receptor blocker, valsartan, inhibited atherosclerotic lesion formation, superoxide production, NADPH oxidase activity, and p47phox expression; these inhibitory effects were significantly weaker in AT2/ApoE-KO mice. We further examined the signaling mechanism of the AT2 receptor-mediated antioxidative effect in cultured fetal vascular smooth muscle cells. NADPH oxidase activity and phosphorylation and translocation of p47phox induced by Ang II were inhibited by valsartan but enhanced by an AT2 receptor blocker, PD123319.

CONCLUSIONS

These results suggest that AT2 receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT2 receptor stimulation by unbound Ang II.

Authors+Show Affiliations

Division of Medical Biochemistry and Cardiovascular Biology, Department of Molecular and Cellular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16145000

Citation

Iwai, Masaru, et al. "Deletion of Angiotensin II Type 2 Receptor Exaggerated Atherosclerosis in Apolipoprotein E-null Mice." Circulation, vol. 112, no. 11, 2005, pp. 1636-43.
Iwai M, Chen R, Li Z, et al. Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice. Circulation. 2005;112(11):1636-43.
Iwai, M., Chen, R., Li, Z., Shiuchi, T., Suzuki, J., Ide, A., Tsuda, M., Okumura, M., Min, L. J., Mogi, M., & Horiuchi, M. (2005). Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice. Circulation, 112(11), 1636-43.
Iwai M, et al. Deletion of Angiotensin II Type 2 Receptor Exaggerated Atherosclerosis in Apolipoprotein E-null Mice. Circulation. 2005 Sep 13;112(11):1636-43. PubMed PMID: 16145000.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice. AU - Iwai,Masaru, AU - Chen,Rui, AU - Li,Zhen, AU - Shiuchi,Tetsuya, AU - Suzuki,Jun, AU - Ide,Ayumi, AU - Tsuda,Masahiro, AU - Okumura,Midori, AU - Min,Li-Juan, AU - Mogi,Masaki, AU - Horiuchi,Masatsugu, Y1 - 2005/09/06/ PY - 2005/9/8/pubmed PY - 2006/2/24/medline PY - 2005/9/8/entrez SP - 1636 EP - 43 JF - Circulation JO - Circulation VL - 112 IS - 11 N2 - BACKGROUND: The role of angiotensin II (Ang II) type 2 (AT2) receptor in atherosclerosis was explored with the use of AT2 receptor/apolipoprotein E (ApoE)-double-knockout (AT2/ApoE-DKO) mice, with a focus on oxidative stress. METHODS AND RESULTS: After treatment with a high-cholesterol diet (1.25% cholesterol) for 10 weeks, ApoE-knockout (KO) mice developed atherosclerotic lesions in the aorta. In AT2/ApoE-DKO mice receiving a high-cholesterol diet, the atherosclerotic changes were further exaggerated, without significant changes in plasma cholesterol level and blood pressure. In the atherosclerotic lesion, an increase in superoxide production, NADPH oxidase activity, and expression of p47phox was observed. These changes were also greater in AT2/ApoE-DKO mice. An Ang II type 1 (AT1) receptor blocker, valsartan, inhibited atherosclerotic lesion formation, superoxide production, NADPH oxidase activity, and p47phox expression; these inhibitory effects were significantly weaker in AT2/ApoE-KO mice. We further examined the signaling mechanism of the AT2 receptor-mediated antioxidative effect in cultured fetal vascular smooth muscle cells. NADPH oxidase activity and phosphorylation and translocation of p47phox induced by Ang II were inhibited by valsartan but enhanced by an AT2 receptor blocker, PD123319. CONCLUSIONS: These results suggest that AT2 receptor stimulation attenuates atherosclerosis through inhibition of oxidative stress and that the antiatherosclerotic effect of valsartan could be at least partly due to AT2 receptor stimulation by unbound Ang II. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/16145000/Deletion_of_angiotensin_II_type_2_receptor_exaggerated_atherosclerosis_in_apolipoprotein_E_null_mice_ L2 - https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.104.525550?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -