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• W1979520023 abstract "JE is a member of the family of “immediate early” genes induced by growth factors and cytokines.JE encodes a low molecular weight secretory glycoprotein analogous to the human monocyte chemoattractant protein, MCP-1. JE and MCP-1 proteins are thought to play an important role in inflammation and in the recruitment of monocyte/macrophages to the vessel wall during the development of atherosclerosis. We have previously reported that the induction of JE in rat aortic smooth muscle cells (SMC) was specific to platelet-derived growth factor (PDGF) and was not seen with other growth agonists. Using a luciferase reporter system and transient transfection assays of rat aortic SMC, we now report the identification of a region in the proximal rat JE promoter that is responsive to PDGF but not to other growth factors (angiotensin II and α-thrombin) or cytokines (interleukin 1-β and tumor necrosis factor-α). The full response to PDGF (∼6-fold) requires the cooperative activity of two potentially novel cis-acting elements, at positions −146 to −128 and −84 to −59. While each element produces a different pattern in electrophoretic mobility shift assays, they appear to bind the same PDGF-responsive species. Further analysis of these regions should provide important insights into PDGF-specific responses in vascular SMC. JE is a member of the family of “immediate early” genes induced by growth factors and cytokines.JE encodes a low molecular weight secretory glycoprotein analogous to the human monocyte chemoattractant protein, MCP-1. JE and MCP-1 proteins are thought to play an important role in inflammation and in the recruitment of monocyte/macrophages to the vessel wall during the development of atherosclerosis. We have previously reported that the induction of JE in rat aortic smooth muscle cells (SMC) was specific to platelet-derived growth factor (PDGF) and was not seen with other growth agonists. Using a luciferase reporter system and transient transfection assays of rat aortic SMC, we now report the identification of a region in the proximal rat JE promoter that is responsive to PDGF but not to other growth factors (angiotensin II and α-thrombin) or cytokines (interleukin 1-β and tumor necrosis factor-α). The full response to PDGF (∼6-fold) requires the cooperative activity of two potentially novel cis-acting elements, at positions −146 to −128 and −84 to −59. While each element produces a different pattern in electrophoretic mobility shift assays, they appear to bind the same PDGF-responsive species. Further analysis of these regions should provide important insights into PDGF-specific responses in vascular SMC. vascular smooth muscle cell(s) platelet-derived growth factor angiotensin II smooth muscle cell(s) Dulbecco's modified Eagle's medium base pair(s) electrophoretic mobility shift assay interleukin tumor necrosis factor α. Growth and migration of vascular smooth muscle cells (VSMC)1 are critical events in the pathogenesis of atherosclerosis, hypertension, and angiogenesis (1Ross R. Nature. 1993; 362: 801-809Crossref PubMed Scopus (9925) Google Scholar). VSMC exhibit two types of growth: hyperplasia, characterized by increased DNA and protein synthesis as well as cell division, and hypertrophy, characterized by increased cell size and protein content without DNA synthesis or cell division (2Owens G.K. Am. J. Physiol. 1989; 257: H1755-H1765PubMed Google Scholar). VSMC hyperplasia is an important feature of atherogenesis and involves the migration of VSMC from the vessel media to the intima and the proliferation of medial and intimal VSMC (1Ross R. Nature. 1993; 362: 801-809Crossref PubMed Scopus (9925) Google Scholar). VSMC hypertrophy is more typical of the vascular response to chronic hypertension, although hyperplasia is seen in hypertension as well (2Owens G.K. Am. J. Physiol. 1989; 257: H1755-H1765PubMed Google Scholar). The growth responses of cultured VSMC appear to be agonist-specific. In adult rat aortic VSMC, platelet-derived growth factor (PDGF) and serum induce hyperplasia (3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar). In the same cells, angiotensin II (Ang) and α-thrombin induce hypertrophy (3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar, 4Schwartz S.M. Heimark R.L. Majesky M.W. Physiol. Rev. 1990; 70: 1177-1209Crossref PubMed Scopus (392) Google Scholar, 5Geisterfer A.A.T. Peach M.J. Owens G.K. Circ. Res. 1988; 62: 749-756Crossref PubMed Scopus (1006) Google Scholar, 6Berk B.C. Vekshtein V. Gordon H.M. Tsuda T. Hypertension. 1989; 13: 305-314Crossref PubMed Scopus (516) Google Scholar, 7Geisterfer A. Owens G. Hypertension. 1989; 14: 413-420Crossref PubMed Scopus (77) Google Scholar, 8Holycross B. Peach M. Owens G. J. Vasc. Res. 1993; 30: 80-86Crossref PubMed Scopus (40) Google Scholar, 9Rothman A. Wolner B. Button D. Taylor P. J. Biol. Chem. 1994; 269: 6399-6404Abstract Full Text PDF PubMed Google Scholar).There is a considerable body of literature involving the response of SMC to PDGF and Ang (reviewed in Refs. 3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar and 10Bernstein K.E. Berk B.C. Am. J. Kidney Dis. 1993; 22: 745-754Abstract Full Text PDF PubMed Scopus (86) Google Scholar). Ang and PDGF activate many of the same intracellular signals, including the activation of phospholipase C, the induction of the mitogen-activated protein kinase cascade, and the activation of the Na+-H+antiporter, and induce similar sets of early response genes (reviewed in Refs. 3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar and 10Bernstein K.E. Berk B.C. Am. J. Kidney Dis. 1993; 22: 745-754Abstract Full Text PDF PubMed Scopus (86) Google Scholar). Attempts by this laboratory to identify differences in gene expression in response to Ang and PDGF using differential screening or high resolution two-dimensional protein gels (11Patton W.F. Erdjument-Bromage H. Marks A.R. Tempst P. Taubman M.B. J. Biol. Chem. 1995; 270: 21404-21410Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 12Green R.S. Lieb M.E. Weintraub A.S. Rosenfield C.L. Gacheru S.N. Shah S. Taubman M.B. Lab. Invest. 1995; 73: 476-482PubMed Google Scholar) have been unsuccessful, underscoring the similarities in signaling and gene induction between the two agonists. These studies suggest that there are a limited number of molecular events that distinguish the hypertrophic and hyperplastic responses of VSMC.JE is a member of the family of “immediate early” genes (13Herschman H.R. Annu. Rev. Biochem. 1991; 60: 281-319Crossref PubMed Scopus (943) Google Scholar) induced by growth factors in various cell types, including macrophages, endothelial cells, fibroblasts, and vascular SMC (14Rollins B.J. Morrison E.D. Stiles C.D. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 3738-3742Crossref PubMed Scopus (369) Google Scholar, 15Yu S.-F. Koerner T.J. Adams D.O. J. Leukocyte Biol. 1990; 48: 412-419Crossref PubMed Scopus (47) Google Scholar, 16Introna M. Bast R.C. Tannenbaum C.S. Hamilton T.A. Adams D.O. J. Immunol. 1987; 138: 3891-3896PubMed Google Scholar, 17Shyy Y.-J. Li Y.-S. Kolattukudy P.E. Biochem. Biophys. Res. Commun. 1990; 169: 346-351Crossref PubMed Scopus (103) Google Scholar, 18Rollins B.J. Yoshimura T. Leonard E.J. Pober J.S. Am. J. Pathol. 1990; 136: 1229-1233PubMed Google Scholar, 19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). The JE product is a secretory glycoprotein of the “C-C” chemokine subfamily (20Rollins B.J. Cancer Cells. 1991; 3: 517-524PubMed Google Scholar) that appears to be the analog of the human monocyte chemoattractant protein, MCP-1 (21Yoshimura T. Yuhki N. Moore S.K. Appella E. Lerman M.I. Leonard E.J. FEBS Lett. 1989; 244: 487-493Crossref PubMed Scopus (485) Google Scholar). JE/MCP-1 protein has been identified in early human atherosclerotic lesions (22Takeya M. Yoshimura T. Leonard E.J. Takahashi K. Hum. Pathol. 1993; 24: 534-539Crossref PubMed Scopus (245) Google Scholar) and has also been found in smooth muscle cells and macrophages of advanced human, primate, and rabbit atherosclerotic plaques (2Owens G.K. Am. J. Physiol. 1989; 257: H1755-H1765PubMed Google Scholar, 23Nelken N.A. Coughlin S.R. Gordon D. Wilcox J.N. J. Clin. Invest. 1991; 88: 1121-1127Crossref PubMed Google Scholar, 24Yla-Herttuala S. Lipton B.A. Rosenfeld M.E. Sarkioja T. Yoshimura T. Leonard E.J. Witztum J.L. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 5252-5256Crossref PubMed Scopus (801) Google Scholar, 25Yu X. Dluz S. Graves D.T. Zhang L. Antoniades H.N. Hollander W. Prusty S. Valente A.J. Schwartz C.J. Sonenshein G.E. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6953-6957Crossref PubMed Scopus (208) Google Scholar, 26Wilcox J.N. J. Vasc. Surg. 1992; 15: 913-915Abstract Full Text PDF PubMed Scopus (21) Google Scholar). JEmRNA is also induced in the media within hours of experimental rodent balloon arterial injury (19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). While numerous agents have been shown to have monocyte chemotactic activity, JE/MCP-1 appears to account for all of the monocyte chemotactic activity secreted by cultured rat (27Poon M. Hsu W.C. Zhang H. Bogdanov V.Y. Taubman M.B. Am. J. Pathol. 1996; 149: 307-317PubMed Google Scholar) and human (28Cushing S.D. Berliner J.A. Valente A.J. Territo M.C. Navab M. Parhami F. Gerrity R. Schwartz C.J. Fogelman A.M. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 5134-5138Crossref PubMed Scopus (960) Google Scholar) SMC in response to PDGF or oxidized low density lipoprotein, respectively. JE/MCP-1 may thus play a particularly important role in SMC-mediated monocyte recruitment during the development of atherosclerosis and in acute vessel injury (29Schwartz C.J. Valente A.J. Sprague E.A. Kelley J.L. Nerem R.M. Clin. Cardiol. 1991; 14: 11-16Crossref PubMed Scopus (243) Google Scholar).We have previously examined the expression of JE mRNA and protein in rat aortic SMC (19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). In contrast to other cell types, where the induction of JE mRNA is common to a variety of growth agonists, the induction of JE mRNA and chemotactic activity in rat aortic SMC was specific to calf serum and PDGF and was not seen with other agonists, including Ang or α-thrombin (19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). In addition, the induction of JE mRNA by PDGF appears to be independent of activation of protein kinase C, mobilization of intracellular calcium, or stimulation of the Na+-H+ exchanger, signals shared by Ang and PDGF and often involved in the induction of immediate early genes in SMC (19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). Accordingly, we have employed the rat JE gene as a model system for identifying potential pathways that differentiate the response to Ang and PDGF. We now report the identification of two sites in the rat JE promoter that act synergistically to regulateJE transcription in a PDGF-specific manner. These sites do not include previously identified PDGF-responsive elements and therefore may be part of a novel PDGF-specific pathway. Such pathways may be involved in differentiating the hypertrophic and hyperplastic phenotypes.DISCUSSIONPrevious studies from this laboratory have demonstrated that the accumulation of JE mRNA and the induction of chemotactic activity in rat aortic SMC is specific for PDGF and is not induced by a variety of other growth factors or cytokines known to be active in these cells (27Poon M. Hsu W.C. Zhang H. Bogdanov V.Y. Taubman M.B. Am. J. Pathol. 1996; 149: 307-317PubMed Google Scholar). This paper describes the first analysis of theJE promoter in SMC and reports the identification of a PDGF-responsive area (−146 to −59) in the proximal rat JEpromoter. In addition, it demonstrates that this area has high specificity for PDGF and suggests that this may be responsible for the PDGF-specific accumulation of JE mRNA seen in rat SMC.The full response to PDGF (∼6-fold) appears to require the cooperative activity of two cis-acting elements at positions −146 to −128 (element 1) and −84 to −59 (element 2). Either element alone is sufficient to confer PDGF-specific inducibility on a luciferase reporter construct, although the level of luciferase activity is ∼50% of that seen with constructs containing both elements. Element 1 has no activity in the antisense orientation when placed immediately upstream of element 2 or when placed upstream of the AP-1-like site in the absence of element 2. Its ability to confer full activity to element 2-containing constructs thus appears to be dependent upon its position and orientation.Element 2 generates two major bands on EMSA. The amount of the slower moving species does not change significantly in response to PDGF, suggesting that the observed DNA-protein interaction is constitutive. In contrast, a faster moving species appears rapidly in response to PDGF but not Ang. As suggested by the deletion analyses, this species is likely to be of paramount importance in the PDGF-specific induction of JE. Element 1 also binds several species, one of which is responsive to PDGF and may be the same PDGF-responsive species bound by element 2. The appearance of the PDGF-responsive species has a time course consistent with the nuclear run-on experiments. Of note, no early binding is seen in response to Ang, but some binding is seen 1 h after Ang treatment. This later appearance may reflect secondary, rather than direct, effects of Ang receptor stimulation and apparently is not sufficient for inducing the JE promoter. Further studies will be necessary to fully characterize the mechanism(s) by which elements 1 and 2 cooperate in regulatingJE promoter activity.It should be stressed that the studies presented above do not establish the precise boundaries of the PDGF-responsive elements. As shown in Fig. 6, mutations in any region of element 2 abolished the activity. This suggests that the entire sequence may be necessary for binding. Preliminary gel shifts (data not shown) with the mutations examined in Fig. 6 showed that disruption of any part of the molecule resulted in a loss of the PDGF-responsive band. Given the complexity of the binding patterns for both elements and the presence of several species that are bound constitutively, it is highly likely that the PDGF effect requires the interaction of several proteins bound to different regions of the elements. The lack of effect of antibodies to c-Jun/AP-1 or Ets-1/Ets-2 on the binding of the PDGF-responsive species raises the possibility that the protein(s) involved may be different from those previously shown to mediate PDGF responses or to regulate the JE orMCP-1 genes.Searches of GenBankTM (release 90.0, 8/95), EMBL (release 43.0, 6/95), and Eukaryotic Promoter (release 43, 6/95) data bases with both putative elements and the entire fragment containing both elements suggest that the sequences conveying PDGF specificity may be novel. Element 1 has high homology (>70% identity) to a 5′-flanking region of Mus musculus cathepsin B (accession number X76621) and to areas in the promoter regions of Aspergillus niger PX18 (accession number M90701), Homo sapiens gastrin (accession number EDP 25015), and M. musculus keratin (accession number EDP 32005). Element 2 has high homology only with sequences in the 5′ region of the murine macrophage inflammatory protein 2 gene. Macrophage inflamatory protein 2 protein is a cytokine with potent chemotactic activity for human polymorphonuclear leukocytes (42Tekamp-Olson P. Gallegos C. Bauer D. McClain J. Sherry B. Fabre M. van Deventer S. Cerami A. J. Exp. Med. 1990; 172: 911-919Crossref PubMed Scopus (247) Google Scholar, 43Huang S. Paulauskis J.D. Godleski J.J. Kobzik L. Am. J. Pathol. 1992; 141: 981-988PubMed Google Scholar). Interestingly, none of the genes identified contain areas of high homology with both elements, and searches of the literature did not provide evidence that these genes were PDGF-responsive. No regions highly homologous to either element exist in the human MCP-1gene, suggesting that they may be species-specific. It should be noted that while PDGF and MCP-1 have been co-localized in human plaques (23Nelken N.A. Coughlin S.R. Gordon D. Wilcox J.N. J. Clin. Invest. 1991; 88: 1121-1127Crossref PubMed Google Scholar,26Wilcox J.N. J. Vasc. Surg. 1992; 15: 913-915Abstract Full Text PDF PubMed Scopus (21) Google Scholar), the regulation of MCP-1 by PDGF in human SMC has not as yet been described.Regulatory elements in the promoter regions of JE/MCP-1genes have been identified by several groups of investigators (34Timmers H.T.M. Pronk G.J. Bos J.L. van der Eb A.J. Nucleic Acids Res. 1990; 18: 23-34Crossref PubMed Scopus (63) Google Scholar,44Li Y.-S. Kolattukudy P.E. Mol. Cell. Biochem. 1994; 141: 121-128Crossref PubMed Scopus (20) Google Scholar, 45Freter R.R. Irminger J.-C. Porter J.A. Jones S.D. Stiles C.D. Mol. Cell. Biol. 1992; 12: 5288-5300Crossref PubMed Scopus (74) Google Scholar, 46Freter R.R. Alberta J.A. Lam K.K. Stiles C.D. Mol. Cell. Biol. 1995; 15: 315-325Crossref PubMed Google Scholar). Timmers et al. (34Timmers H.T.M. Pronk G.J. Bos J.L. van der Eb A.J. Nucleic Acids Res. 1990; 18: 23-34Crossref PubMed Scopus (63) Google Scholar) established that the −70/−38 region of the rat JE promoter was necessary for its basal activity in transiently transfected 3T3 cells and established that the region −141/−88 was essential for the response to the phorbol ester TPA. Our study also suggests that the AP-1-like site located within the −70/−38 region is necessary for basal promoter activity in rat aortic SMC. Li and Kolattukudy (44Li Y.-S. Kolattukudy P.E. Mol. Cell. Biochem. 1994; 141: 121-128Crossref PubMed Scopus (20) Google Scholar) established that two elements (at positions −156 to −150 and −128 to −123) in the promoter region of human MCP-1 were necessary and sufficient to confer inducibility by TPA onto a CAT reporter construct transiently expressed in human glioblastoma cells. Activation of human MCP-1 by TNFα occurred via different cis-acting elements, because TNFα did not activate the TPA-inducible reporter constructs.Freter et al. (45Freter R.R. Irminger J.-C. Porter J.A. Jones S.D. Stiles C.D. Mol. Cell. Biol. 1992; 12: 5288-5300Crossref PubMed Scopus (74) Google Scholar) identified two cis-acting regions that were necessary for the activation of the murineJE gene by serum, PDGF, IL-1, and double-stranded RNA in transiently transfected BALB/c 3T3 fibroblasts. That study did not demonstrate activation of reporter constructs and utilized RNase protection assays with a series of tagged genomic JE probes. The distal 240-bp sequence in the 5′-flanking JE region (positions −2537 to −2298 relative to the start site) had weak transcriptional enhancer activity. The other element identified in the study was a novel 7-mer, TTTTGTA, located in the 3′ region of the murine JE after the stop codon. Its activity was position-dependent and orientation independent. The 7-mer is present in 3′ regions of a number of transcription factors and cytokines belonging to the immediate early gene class, including humanMCP-1. In follow-up studies (46Freter R.R. Alberta J.A. Lam K.K. Stiles C.D. Mol. Cell. Biol. 1995; 15: 315-325Crossref PubMed Google Scholar, 47Freter R.R. Alberta J.A. Hwang G.Y. Wrentmore A.L. Stiles C.D. J. Biol. Chem. 1996; 271: 17417-17424Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar), four PDGF-regulated elements were identified within the region located in the 240-bp 5′-flanking murine JE sequences. Two of these elements (I and IV) are similar in sequence and bind several forms of NF-κB. The other two elements (II and III) were previously uncharacterized sequences that bind a PDGF-activated serine-threonine phosphoprotein found in the nucleus of PDGF-treated 3T3 fibroblasts.In the rat JE gene, murine elements I and IV are not present. There is a region in the rat JE promoter (positions −472 to −449) with a 72% homology to murine element II in reverse orientation; however, our data indicate that the presence of this region is not required for activation of JE in SMC by PDGF. The rat JE gene also possesses a region with 69.2% homology to murine element III in reverse orientation; this region is located 15 bp downstream of the initiation codon. Thus, the pathways that lead to transcriptional induction by PDGF of JE in mouse appear to be different from those in rat and may also be different in SMC from other cell types.We have previously reported that changes in mRNA stability were responsible for part of the increase in JE mRNA levels seen after PDGF treatment (19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). In that study, nuclear run-on experiments, performed at 1 and 2 h, did not suggest a major transcriptional component. These time points were originally chosen because of the delayed peak in JE mRNA levels. The current study employed considerably earlier time points (15 and 30 min) to examine JE transcription. Using these time points, PDGF was found to cause a marked but very transient increase in JE transcription. Taken together, these studies suggest that the initial response to PDGF is an elevation in transcription, which is short lived. This is accompanied by an increase in mRNA stability (half-life of 2.5 versus 0.5 h), resulting in a prolonged elevation in JE mRNA levels beyond that seen with other immediate early genes.As noted in the Introduction, the intracellular signaling pathways responsible for JE mRNA accumulation in rat aortic SMC remain to be determined. Initial studies employing RNA blot analyses and a variety of inhibitors failed to demonstrate a role for protein kinase C, mobilization of intracellular calcium, activation of the Na+-H+ exchanger, and changes in cyclic AMP (19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). While these studies were by no means exhaustive and do not rule out participation of any of these signals, they do suggest that the induction of JE mRNA in rat aortic SMC by PDGF involves signaling pathways distinct from those involved in the induction of a number of other immediate early genes in rat SMC, including c-fos, KC, and tissue factor (30Taubman M.B. Marmur J.D. Rosenfield C.-L. Guha A. Nichtberger S. Nemerson Y. J. Clin. Invest. 1993; 91: 547-552Crossref PubMed Scopus (162) Google Scholar, 48Taubman M.B. Berk B.C. Izumo S. Tsuda T. Alexander R.W. Nadal-Ginard B. J. Biol. Chem. 1989; 264: 526-530Abstract Full Text PDF PubMed Google Scholar, 49Marmur J.D. Poon M. Rossikhina M. Taubman M.B. Circulation. 1992; 86: 53-60Google Scholar). The current study, demonstrating potentially novel PDGF-specific elements in the rat JE gene, gives further credence to the concept that the regulation of JE in rat aortic SMC may involve an unusual set of signaling pathways.PDGF and Ang have been implicated in the development of atherosclerosis, in the response of the vessel wall to injury, and in the vascular changes associated with hypertension (1Ross R. Nature. 1993; 362: 801-809Crossref PubMed Scopus (9925) Google Scholar, 2Owens G.K. Am. J. Physiol. 1989; 257: H1755-H1765PubMed Google Scholar, 50Dzau V.J. J. Hypertension. 1994; 12: S3-10Google Scholar). While considerable information exists about the signals induced in VSMC by PDGF and Ang, the induction of JE remains one of the few phenomena described that distinguish the early response of adult rat aortic VSMC to these two agonists. JE/MCP-1 protein appears to function chiefly as a monocyte chemoattractant and has not been shown to be a mitogen. It is therefore unlikely that JE/MCP-1 is directly responsible for the difference between PDGF-induced hyperplasia and Ang-induced hypertrophy. Dissection of the rat JE promoter in SMC and identification of the proteins that bind to the PDGF-responsive elements may help elucidate PDGF-specific pathways. This may provide powerful tools for identifying downstream signals that differentiate PDGF- and Ang-induced transcription and may be involved in differentiating the growth responses. Growth and migration of vascular smooth muscle cells (VSMC)1 are critical events in the pathogenesis of atherosclerosis, hypertension, and angiogenesis (1Ross R. Nature. 1993; 362: 801-809Crossref PubMed Scopus (9925) Google Scholar). VSMC exhibit two types of growth: hyperplasia, characterized by increased DNA and protein synthesis as well as cell division, and hypertrophy, characterized by increased cell size and protein content without DNA synthesis or cell division (2Owens G.K. Am. J. Physiol. 1989; 257: H1755-H1765PubMed Google Scholar). VSMC hyperplasia is an important feature of atherogenesis and involves the migration of VSMC from the vessel media to the intima and the proliferation of medial and intimal VSMC (1Ross R. Nature. 1993; 362: 801-809Crossref PubMed Scopus (9925) Google Scholar). VSMC hypertrophy is more typical of the vascular response to chronic hypertension, although hyperplasia is seen in hypertension as well (2Owens G.K. Am. J. Physiol. 1989; 257: H1755-H1765PubMed Google Scholar). The growth responses of cultured VSMC appear to be agonist-specific. In adult rat aortic VSMC, platelet-derived growth factor (PDGF) and serum induce hyperplasia (3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar). In the same cells, angiotensin II (Ang) and α-thrombin induce hypertrophy (3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar, 4Schwartz S.M. Heimark R.L. Majesky M.W. Physiol. Rev. 1990; 70: 1177-1209Crossref PubMed Scopus (392) Google Scholar, 5Geisterfer A.A.T. Peach M.J. Owens G.K. Circ. Res. 1988; 62: 749-756Crossref PubMed Scopus (1006) Google Scholar, 6Berk B.C. Vekshtein V. Gordon H.M. Tsuda T. Hypertension. 1989; 13: 305-314Crossref PubMed Scopus (516) Google Scholar, 7Geisterfer A. Owens G. Hypertension. 1989; 14: 413-420Crossref PubMed Scopus (77) Google Scholar, 8Holycross B. Peach M. Owens G. J. Vasc. Res. 1993; 30: 80-86Crossref PubMed Scopus (40) Google Scholar, 9Rothman A. Wolner B. Button D. Taylor P. J. Biol. Chem. 1994; 269: 6399-6404Abstract Full Text PDF PubMed Google Scholar). There is a considerable body of literature involving the response of SMC to PDGF and Ang (reviewed in Refs. 3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar and 10Bernstein K.E. Berk B.C. Am. J. Kidney Dis. 1993; 22: 745-754Abstract Full Text PDF PubMed Scopus (86) Google Scholar). Ang and PDGF activate many of the same intracellular signals, including the activation of phospholipase C, the induction of the mitogen-activated protein kinase cascade, and the activation of the Na+-H+antiporter, and induce similar sets of early response genes (reviewed in Refs. 3Ross R. Raines E.W. Bowen-Pope D.F. Cell. 1986; 46: 155-169Abstract Full Text PDF PubMed Scopus (1573) Google Scholar and 10Bernstein K.E. Berk B.C. Am. J. Kidney Dis. 1993; 22: 745-754Abstract Full Text PDF PubMed Scopus (86) Google Scholar). Attempts by this laboratory to identify differences in gene expression in response to Ang and PDGF using differential screening or high resolution two-dimensional protein gels (11Patton W.F. Erdjument-Bromage H. Marks A.R. Tempst P. Taubman M.B. J. Biol. Chem. 1995; 270: 21404-21410Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 12Green R.S. Lieb M.E. Weintraub A.S. Rosenfield C.L. Gacheru S.N. Shah S. Taubman M.B. Lab. Invest. 1995; 73: 476-482PubMed Google Scholar) have been unsuccessful, underscoring the similarities in signaling and gene induction between the two agonists. These studies suggest that there are a limited number of molecular events that distinguish the hypertrophic and hyperplastic responses of VSMC. JE is a member of the family of “immediate early” genes (13Herschman H.R. Annu. Rev. Biochem. 1991; 60: 281-319Crossref PubMed Scopus (943) Google Scholar) induced by growth factors in various cell types, including macrophages, endothelial cells, fibroblasts, and vascular SMC (14Rollins B.J. Morrison E.D. Stiles C.D. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 3738-3742Crossref PubMed Scopus (369) Google Scholar, 15Yu S.-F. Koerner T.J. Adams D.O. J. Leukocyte Biol. 1990; 48: 412-419Crossref PubMed Scopus (47) Google Scholar, 16Introna M. Bast R.C. Tannenbaum C.S. Hamilton T.A. Adams D.O. J. Immunol. 1987; 138: 3891-3896PubMed Google Scholar, 17Shyy Y.-J. Li Y.-S. Kolattukudy P.E. Biochem. Biophys. Res. Commun. 1990; 169: 346-351Crossref PubMed Scopus (103) Google Scholar, 18Rollins B.J. Yoshimura T. Leonard E.J. Pober J.S. Am. J. Pathol. 1990; 136: 1229-1233PubMed Google Scholar, 19Taubman M.B. Rollins B.J. Poon M. Marmur J. Green R.S. Berk B.C. Nadal-Ginard B. Circ. Res. 1992; 70: 314-325Crossref PubMed Google Scholar). The JE product is a secretory glycoprotein of the “C-C” chemokine subfamily (20Rollins B.J. Cancer Cells. 1991; 3: 517-524PubMed Google Scholar) that appears to be the analog of the human monocyte" @default.
• W1979520023 created "2016-06-24" @default.
• W1979520023 creator A5018617417 @default.
• W1979520023 creator A5046314701 @default.
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