Post-transcriptional regulation of placenta growth factor mRNA by hydrogen peroxide.
In tissues containing pre-existing collateral vessels, occlusion of an upstream supply artery results in diversion of blood flow through these vessels, protecting the distal tissue from ischemia. The sudden rise in blood flow through collateral vessels exerts shear stress upon the vessel wall, thereby providing the initial stimulus for arteriogenesis. Arteriogenesis, the structural expansion of collateral circulation, involves smooth muscle cell (SMC) proliferation which leads to increased vessel diameter and wall thickness. Since shear is sensed at the level of endothelial cells (EC), communication from EC to the underlying SMC must occur as part of this process. We previously reported that endothelial cells (EC) exposed to shear stress release hydrogen peroxide (H(2)O(2)), and that H(2)O(2) can signal vascular SMC to increase gene and protein expression of placenta growth factor (PLGF), a known mediator of arteriogenesis. The purpose of the current study was to further elucidate the mechanism whereby PLGF is regulated by H(2)O(2). We found that a single, physiological dose of H(2)O(2) increases PLGF mRNA half-life, but has no effect on PLGF promoter activity, in human coronary artery SMC (CASMC). We further demonstrated that the H(2)O(2)-induced increase in PLGF mRNA levels partially relies on p38 MAPK, JNK and ERK1/2 pathways. Finally, we showed that chronic exposure to pathological levels of H(2)O(2) further increases PLGF mRNA levels, but does not result in a corresponding increase in PLGF secreted protein. These data suggest that PLGF regulation has an important translational component. To our knowledge, this is the first study to characterize post-transcriptional regulation of PLGF mRNA by H(2)O(2) in vascular SMC. These findings provide new insights into the regulation of this important growth factor and increase our understanding of PLGF-driven arteriogenesis.
Department of Physiological Sciences, Oklahoma State University, Stillwater, OK 74078, USA.
Jennifer H
JH
Shaw
Pamela G
PG
Lloyd
D000841:Anisomycin / Q000494:pharmacology; D002478:Cells, Cultured; D002648:Child; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D020536:Enzyme Activators; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D000072483:Placenta Growth Factor; D000841:Anisomycin; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases