Ang Ii Induces Apoptosis of Human Vascular Smooth Muscle Via Extrinsic Pathway Involving Inhibition of Akt Phosphorylation and Increased Fasl Expression.
From: Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112-2699, USA.
American journal of physiology. Heart and circulatory physiology
- Publish Date: May 2006
- ISSN: 0363-6135
- Volume: 290
- Issue: 5
- Pages: H2116-23
- Medium: Print
- Language: English
- Citation (JAMA): Li Yangxin, Song Yao-Hua, Mohler Jessica, et al. Ang Ii Induces Apoptosis of Human Vascular Smooth Muscle Via Extrinsic Pathway Involving Inhibition of Akt Phosphorylation and Increased Fasl Expression.. Am. J. Physiol. Heart Circ. Physiol. May 2006;290:H2116-23
Abstract
In addition to well-documented vascular growth-promoting effects, ANG II exerts proapoptotic effects that are poorly understood. IGF-1 is a potent survival factor for human vascular smooth muscle cells (hVSMC), and its antiapoptotic effects are mediated via the IGF-1 receptor (IGF-1R) through a signaling pathway involving phosphatidylinositol 3-kinase and Akt. We hypothesized that there would be cross talk between ANG II proapoptotic effects and IGF-1 survival effects in hVSMC. To investigate ANG II-induced apoptosis and the potential involvement of IGF-1, we exposed quiescent and nonquiescent hVSMC to ANG II. ANG II induced apoptosis only in nonquiescent cells but stimulated hypertrophy in quiescent cells. ANG II-induced apoptosis was characterized by marked inhibition of Akt phosphorylation and stimulation of membrane Fas ligand (FasL) expression, caspase-8 activation, and a reduction in soluble FasL expression. Adenovirally mediated overexpression of Akt rescued hVSMC from ANG II-induced apoptosis. IGF-1R activation increased Akt phosphorylation and soluble FasL expression, and these effects were completely blocked by coincubating hVSMC with ANG II. In conclusion, ANG II-induced apoptosis of hVSMC is characterized by marked inhibition of Akt phosphorylation and stimulation of an extrinsic cell death signaling pathway via upregulation of membrane FasL expression, caspase-8 activation, and a reduction in soluble FasL expression. Furthermore, ANG II antagonizes the antiapoptotic effect of IGF-1 by blocking its ability to increase Akt phosphorylation and soluble FasL. These findings provide novel insights into ANG II-induced apoptotic signaling and have significant implication for understanding ANG II-induced remodeling in hypertension and atherosclerosis.
Mesh Headings (Keywords): Angiotensin II, Apoptosis, Cells, Cultured, Fas Ligand Protein, Humans, Membrane Glycoproteins, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Oncogene Protein v-akt, Phosphorylation, Signal Transduction, Tumor Necrosis Factors
Check for Full Text / PubMed Unique Identifier (PMID): 16339840
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