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

Abstract

Abstract-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 (AT 1 ) was responsible for these effects. Among the signaling molecules downstream of AT 1 , 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, AT 1a 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 Ⅲ apoptosis Ⅲ endothelium Ⅲ survivin Ⅲ caspase-3 A ngiotensin II (Ang II), the most important effector peptide of the renin-angiotensin system, plays central roles in volume and salt homeostasis. Ang II is implicated in cardiovascular and renal pathology including cardiac left ventricular hypertrophy, neointimal formation, postinfarct vascular remodeling, and nephrosclerosis. 1,2 Apoptosis and cellular proliferation are important mechanisms causing these pathological conditions. In this respect, Ang II has been recognized as a growth-promoting and apoptosis-regulating factor contributing to vascular structural alteration. 3 Ang II initiates its effects by interaction with at least two pharmacologically distinct subtypes of cell-surface receptors, AT 1 and AT 2 . In mice, the AT 1 receptor is further subdivided into AT 1a and AT 1b . Major functions of Ang II in the cardiovascular system are mediated through AT 1 , whereas AT 2 exerts antigrowth and antihypertrophic effects. 4 Ang II activates multiple signaling pathways, including protein kinase C (PKC), 5 and mitogen-activated protein kinase (MAPK). 5 MAPKs are key regulatory proteins that control the cellular response to growth, apoptosis, and stress signals. More recently, stimulation of AT 1 has been shown to trigger the activation of phosphatidylinositol 3 (PI3)-kinase and Akt, 6 which is a common feature in the signal transduction of the antiapoptotic effects of growth factors. Although both MAPK and PI3-kinase/Akt contribute to apoptosis, the precise role of Ang II in apoptosis has been a subject of continuing controversy. Ang II has been reported to induce apoptosis in fibroblasts, 7 cardiomyocytes, 8 ...

Role of endothelial cell apoptosis in regulation of skeletal muscle angiogenesis during high and low salt intake

“…Salt intake is one important physiological factor that regulates renin secretion and consequently ANG II levels. Our data support a recent study (35) that indicates that ANG II plays a critical antiapoptotic role in vascular endothelial cells by interfering with mechanisms involving phosphatidylinositol 3-kinase (PI3-kinase)/Akt activation and survival pathways.…”

Angiotensin II promotes NO production, inhibits apoptosis and enhances adhesion potential of bone marrow-derived endothelial progenitor cells

“…Second, AngII inhibits apoptosis of EPCs under serum starvation conditions, which may help maintain the number of EPCs when they are recruited to ischemic regions. We further investigated the mechanisms underlying this effect by examining the PI3-kinase/Akt pathway, which lies downstream of AT1R [6]. It was found that the pathway also plays an essential role in the AngII-induced antiapoptotic signaling of EPCs.…”

“…AngII inhibits EC apoptosis [6], upregulates adhesion molecules [7] and potently augments endothelial nitric oxide synthase (eNOS) mRNA expression, which thereby increases nitric oxide (NO) release [8]. Therefore, we propose that AngII may have similar effects on EPCs as well.…”

Survivin, a cancer target with an emerging role in normal adult tissues

“…Survivin disruption abrogates the effects induced by angiogenic factors (25), pointing to survivin as a key factor for endothelial cell integrity. Similarly, angiotensin II enhances survival of retinal endothelial cells, which is mediated by up-regulation of survivin through the phosphatidylinositol 3-kinase/Akt pathway and inhibits hyperoxygen-induced retinal regression through survivin in a murine model (66). Apoptosis in human umbilical vascular endothelial cells (HUVEC) is inhibited by angiopoeitin 1 via up-regulation of survivin expression through the forkhead-related transcription factor pathway (67).…”