Role of Angiotensin II–Regulated Apoptosis Through Distinct AT 1 and AT 2 Receptors in Neointimal Formation

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Abstract
Background— In vitro studies suggest that angiotensin II type 1 and type 2 (AT 1 and AT 2 ) 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 AT 2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT 1a in vascular remodeling. Methods and Results— Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT 1a -null (AT 1a KO), AT 2 -null (AT 2 KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT 2 KO mice, but they were both suppressed in AT 1a KO 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 AT 1a KO mice but decreased in AT 2 KO mice. Reverse transcriptase–polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT 2 KO mice. On the other hand, the expression of bcl-2 and bcl-x L mRNA was enhanced in AT 2 KO mice but attenuated in AT 1a KO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results. Conclusions— Our results suggest that AT 2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT 1a in the process of neointimal formation after vascular injury.