Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation.
BACKGROUND
In vitro studies suggest that angiotensin II type 1 and type 2 (AT1 and AT2) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT1a in vascular remodeling.


RESULTS
Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT1a-null (AT1aKO), AT2-null (AT2KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT2KO mice, but they were both suppressed in AT1aKO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT1aKO mice but decreased in AT2KO mice. Reverse transcriptase-polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT2KO mice. On the other hand, the expression of bcl-2 and bcl-x(L) mRNA was enhanced in AT2KO mice but attenuated in AT1aKO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results.


CONCLUSIONS
Our results suggest that AT2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT1a in the process of neointimal formation after vascular injury.
Suzuki
Jun
J
Department of Medical Biochemistry, Ehime University School of Medicine, Ehime, Japan.
Iwai
Masaru
M
Nakagami
Hironori
H
Wu
Lan
L
Chen
Rui
R
Sugaya
Takashi
T
Hamada
Mareomi
M
Hiwada
Kunio
K
Horiuchi
Masatsugu
M
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002452:Cell Count; D002455:Cell Division; D003251:Constriction, Pathologic; D004247:DNA / Q000096:biosynthesis; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D014654:Vascular Patency; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000804:Angiotensin II; D004247:DNA