Published online before print February 12, 2004, doi: 10.1161/01.RES.0000121103.03275.EC
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Submitted on August 21, 2003
Revised on January 23, 2004
Accepted on January 29, 2004
Phosphatidylinositol 3-Kinase/Akt Regulates Angiotensin II-Induced Inhibition of Apoptosis in Microvascular Endothelial Cells by Governing Survivin Expression and Suppression of Caspase-3 Activity
Hirokazu Ohashi ;
From the Department of Ophthalmology and Visual Sciences Graduate School of Medicine (H. Ohashi, H.T., H. Oh, K.S., I.S., N.M., A.U., D.W., T.M., Y.H.), Kyoto University, Kyoto, Japan; Tanabe Seiyaku Co, Ltd (T.S.), Osaka, Japan; and the Center for Tsukuba Advanced Research Alliance (A.F.), the University of Tsukuba, Ibaraki, Japan.
* To whom correspondence should be addressed. E-mail: hitoshi{at}kuhp.kyoto-u.ac.jp.
Angiotensin II (Ang II) plays essential roles in vascular homeostasis, neointimal formation, and postinfarct remodeling. Although Ang II has been shown to regulate apoptosis in cardiomyocytes and vascular smooth muscle cells, its role in vascular endothelial cells (ECs) remains elusive. To address this issue, we first performed TUNEL and caspase-3 activity assays with porcine microvascular ECs challenged by serum deprivation. Ang II significantly reduced the ratio of apoptotic cells and caspase-3 activity. The Ang II type 1 receptor (AT1) was responsible for these effects. Among the signaling molecules downstream of AT1, we revealed that PI3-kinase/Akt pathway plays a predominant role in the antiapoptotic effect of Ang II. Interestingly, the expression of survivin, a central molecule of cell survival, increased after Ang II stimulation. Overexpression of a dominant-negative form of Akt abolished both Ang II-induced antiapoptosis and survivin protein expression. In a murine model of hyperoxygen-induced retinal vascular regression, receptor AT1a knockout mice showed a significant increase in retinal avascular areas. Our data indicate that Ang II plays a critical antiapoptotic role in vascular ECs by a mechanism involving PI3-kinase/Akt activation, subsequent upregulation of survivin, and suppression of caspase-3 activity.
Key words: angiotensin II • apoptosis • endothelium • survivin • caspase-3
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