title: Angiotensin II regulates phosphoinositide 3 kinase/Akt cascade via a negative crosstalk between AT1 and AT2 receptors in skin fibroblasts of human hypertrophic scars.
abstract: Angiotensin II (Ang II) stimulation has been shown to regulate proliferation of skin fibroblasts and production of extracellular matrix, which are very important process in skin wound healing and scarring; however, the signaling pathways involved in this process, especially in humans, are less explored. In the present study, we used skin fibroblasts of human hypertrophic scar, which expressed both AT1 and AT2 receptors, and observed that Ang II increased Akt phosphorylation and phosphoinositide 3 kinase (PI 3-K) activity. In addition, the Ang II-induced Akt phosphorylation was blocked by wortmannin, a PI 3-K inhibitor. This Ang II-activated PI 3-K/Akt cascade was markedly inhibited by valsartan, an AT(1) receptor-specific blocker, whereas it was enhanced by PD123319, an AT(2) receptor antagonist. On the other hand, the Ang II- or EGF-induced activation of PI 3-K/Akt was strongly attenuated by AG1478, an inhibitor of epidermal growth factor (EGF) receptor kinase. Moreover, Ang II stimulated tyrosine phosphorylation of EGF receptor and p85alpha subunit of PI 3-K accompanied by an increase in their association, which was inhibited by valsartan, and enhanced by PD123319. The Ang II-induced transactivation of EGF receptor resulted in activation of extracellular signal-regulated kinase (ERK) that was also inhibited by valsartan, and enhanced by PD123319. Taken together, our results showed that AT(1) receptor-mediated activation of PI 3-K/Akt cascades occurs at least partially via the transactivation of EGF receptor, which is under a negative control by AT(2) receptor in hypertrophic scar fibroblasts. These findings contribute to understanding the molecular mechanism of human hypertrophic scar formation.
authors.affiliation: Department of Plastic Surgery, Guangzhou Liuhuaqiao Hospital, Liuhua road 111, Guangzhou, Guangdong Province 510010, PR China. liuhongwei0521@hotmail.com
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Liu
authors.forename: Biao
authors.initials: B
authors.lastname: Cheng
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Yu
authors.forename: Rui-Xia
authors.initials: RX
authors.lastname: Sun
authors.forename: Dong
authors.initials: D
authors.lastname: Zeng
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Yuan-Xing
authors.initials: YX
authors.lastname: Liao
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Fu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000166:cytology*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt