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. 1996 Mar 1;97(5):1276–1285. doi: 10.1172/JCI118543

H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells.

D K Han 1, Z Z Khaing 1, R A Pollock 1, C C Haudenschild 1, G Liau 1
PMCID: PMC507181  PMID: 8636440

Abstract

H19 is a developmentally regulated gene with putative tumor suppressor activity, and loss of H19 expression may be involved in Wilms' tumorigenesis. In this report, we have performed in situ hybridization analysis of H19 expression during normal rabbit development and in human atherosclerotic plaques. We have also used cultured smooth muscle cells to identify H19 regulatory factors. Our data indicate that H19 expression in the developing skeletal and smooth muscles correlated with specific differentiation events in these tissues. Expression of H19 in the skeletal muscle correlated with nonproliferative, actin-positive muscle cells. In the prenatal blood vessel, H19 expression was both temporally and spatially regulated with initial loss of expression in the inner smooth muscle layers adjacent to the lumen. We also identified H19-positive cells within the adult atherosclerotic lesion and we suggest that these cells may recapitulate earlier developmental events. These results, along with the identification of the insulin family of growth factors as potent regulatory molecules for H19 expression, provide additional clues toward understanding the physiological regulation and function of H19.

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Selected References

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  1. Aikawa M., Sivam P. N., Kuro-o M., Kimura K., Nakahara K., Takewaki S., Ueda M., Yamaguchi H., Yazaki Y., Periasamy M. Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis. Circ Res. 1993 Dec;73(6):1000–1012. doi: 10.1161/01.res.73.6.1000. [DOI] [PubMed] [Google Scholar]
  2. Bartolomei M. S., Webber A. L., Brunkow M. E., Tilghman S. M. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev. 1993 Sep;7(9):1663–1673. doi: 10.1101/gad.7.9.1663. [DOI] [PubMed] [Google Scholar]
  3. Bartolomei M. S., Zemel S., Tilghman S. M. Parental imprinting of the mouse H19 gene. Nature. 1991 May 9;351(6322):153–155. doi: 10.1038/351153a0. [DOI] [PubMed] [Google Scholar]
  4. Brannan C. I., Dees E. C., Ingram R. S., Tilghman S. M. The product of the H19 gene may function as an RNA. Mol Cell Biol. 1990 Jan;10(1):28–36. doi: 10.1128/mcb.10.1.28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brunkow M. E., Tilghman S. M. Ectopic expression of the H19 gene in mice causes prenatal lethality. Genes Dev. 1991 Jun;5(6):1092–1101. doi: 10.1101/gad.5.6.1092. [DOI] [PubMed] [Google Scholar]
  6. Cercek B., Fishbein M. C., Forrester J. S., Helfant R. H., Fagin J. A. Induction of insulin-like growth factor I messenger RNA in rat aorta after balloon denudation. Circ Res. 1990 Jun;66(6):1755–1760. doi: 10.1161/01.res.66.6.1755. [DOI] [PubMed] [Google Scholar]
  7. Cook C. L., Weiser M. C., Schwartz P. E., Jones C. L., Majack R. A. Developmentally timed expression of an embryonic growth phenotype in vascular smooth muscle cells. Circ Res. 1994 Feb;74(2):189–196. doi: 10.1161/01.res.74.2.189. [DOI] [PubMed] [Google Scholar]
  8. Davis E. C. Smooth muscle cell to elastic lamina connections in developing mouse aorta. Role in aortic medial organization. Lab Invest. 1993 Jan;68(1):89–99. [PubMed] [Google Scholar]
  9. Davis R. L., Weintraub H., Lassar A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987 Dec 24;51(6):987–1000. doi: 10.1016/0092-8674(87)90585-x. [DOI] [PubMed] [Google Scholar]
  10. DeChiara T. M., Robertson E. J., Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell. 1991 Feb 22;64(4):849–859. doi: 10.1016/0092-8674(91)90513-x. [DOI] [PubMed] [Google Scholar]
  11. Gabbiani G., Kocher O., Bloom W. S., Vandekerckhove J., Weber K. Actin expression in smooth muscle cells of rat aortic intimal thickening, human atheromatous plaque, and cultured rat aortic media. J Clin Invest. 1984 Jan;73(1):148–152. doi: 10.1172/JCI111185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Giuriato L., Scatena M., Chiavegato A., Tonello M., Scannapieco G., Pauletto P., Sartore S. Non-muscle myosin isoforms and cell heterogeneity in developing rabbit vascular smooth muscle. J Cell Sci. 1992 Jan;101(Pt 1):233–246. doi: 10.1242/jcs.101.1.233. [DOI] [PubMed] [Google Scholar]
  13. Glukhova M. A., Frid M. G., Koteliansky V. E. Developmental changes in expression of contractile and cytoskeletal proteins in human aortic smooth muscle. J Biol Chem. 1990 Aug 5;265(22):13042–13046. [PubMed] [Google Scholar]
  14. Grant M. B., Wargovich T. J., Ellis E. A., Caballero S., Mansour M., Pepine C. J. Localization of insulin-like growth factor I and inhibition of coronary smooth muscle cell growth by somatostatin analogues in human coronary smooth muscle cells. A potential treatment for restenosis? Circulation. 1994 Apr;89(4):1511–1517. doi: 10.1161/01.cir.89.4.1511. [DOI] [PubMed] [Google Scholar]
  15. Halevy O., Novitch B. G., Spicer D. B., Skapek S. X., Rhee J., Hannon G. J., Beach D., Lassar A. B. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science. 1995 Feb 17;267(5200):1018–1021. doi: 10.1126/science.7863327. [DOI] [PubMed] [Google Scholar]
  16. Han D. K., Liau G. Identification and characterization of developmentally regulated genes in vascular smooth muscle cells. Circ Res. 1992 Sep;71(3):711–719. doi: 10.1161/01.res.71.3.711. [DOI] [PubMed] [Google Scholar]
  17. Hao Y., Crenshaw T., Moulton T., Newcomb E., Tycko B. Tumour-suppressor activity of H19 RNA. Nature. 1993 Oct 21;365(6448):764–767. doi: 10.1038/365764a0. [DOI] [PubMed] [Google Scholar]
  18. Jacks T., Varmus H. E. Expression of the Rous sarcoma virus pol gene by ribosomal frameshifting. Science. 1985 Dec 13;230(4731):1237–1242. doi: 10.1126/science.2416054. [DOI] [PubMed] [Google Scholar]
  19. KARRER H. E. Electron microscope study of developing chick embryo aorta. J Ultrastruct Res. 1960 Dec;4:420–454. doi: 10.1016/s0022-5320(60)80032-9. [DOI] [PubMed] [Google Scholar]
  20. Kim D. K., Zhang L., Dzau V. J., Pratt R. E. H19, a developmentally regulated gene, is reexpressed in rat vascular smooth muscle cells after injury. J Clin Invest. 1994 Jan;93(1):355–360. doi: 10.1172/JCI116967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kocher O., Skalli O., Cerutti D., Gabbiani F., Gabbiani G. Cytoskeletal features of rat aortic cells during development. An electron microscopic, immunohistochemical, and biochemical study. Circ Res. 1985 Jun;56(6):829–838. doi: 10.1161/01.res.56.6.829. [DOI] [PubMed] [Google Scholar]
  22. Kuro-o M., Nagai R., Nakahara K., Katoh H., Tsai R. C., Tsuchimochi H., Yazaki Y., Ohkubo A., Takaku F. cDNA cloning of a myosin heavy chain isoform in embryonic smooth muscle and its expression during vascular development and in arteriosclerosis. J Biol Chem. 1991 Feb 25;266(6):3768–3773. [PubMed] [Google Scholar]
  23. Kuro-o M., Nagai R., Tsuchimochi H., Katoh H., Yazaki Y., Ohkubo A., Takaku F. Developmentally regulated expression of vascular smooth muscle myosin heavy chain isoforms. J Biol Chem. 1989 Nov 5;264(31):18272–18275. [PubMed] [Google Scholar]
  24. Lee J. E., Pintar J., Efstratiadis A. Pattern of the insulin-like growth factor II gene expression during early mouse embryogenesis. Development. 1990 Sep;110(1):151–159. doi: 10.1242/dev.110.1.151. [DOI] [PubMed] [Google Scholar]
  25. Leighton P. A., Ingram R. S., Eggenschwiler J., Efstratiadis A., Tilghman S. M. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature. 1995 May 4;375(6526):34–39. doi: 10.1038/375034a0. [DOI] [PubMed] [Google Scholar]
  26. Liau G., Chan L. M. Regulation of extracellular matrix RNA levels in cultured smooth muscle cells. Relationship to cellular quiescence. J Biol Chem. 1989 Jun 15;264(17):10315–10320. [PubMed] [Google Scholar]
  27. Lustig O., Ariel I., Ilan J., Lev-Lehman E., De-Groot N., Hochberg A. Expression of the imprinted gene H19 in the human fetus. Mol Reprod Dev. 1994 Jul;38(3):239–246. doi: 10.1002/mrd.1080380302. [DOI] [PubMed] [Google Scholar]
  28. Majesky M. W., Giachelli C. M., Reidy M. A., Schwartz S. M. Rat carotid neointimal smooth muscle cells reexpress a developmentally regulated mRNA phenotype during repair of arterial injury. Circ Res. 1992 Oct;71(4):759–768. doi: 10.1161/01.res.71.4.759. [DOI] [PubMed] [Google Scholar]
  29. Miano J. M., Cserjesi P., Ligon K. L., Periasamy M., Olson E. N. Smooth muscle myosin heavy chain exclusively marks the smooth muscle lineage during mouse embryogenesis. Circ Res. 1994 Nov;75(5):803–812. doi: 10.1161/01.res.75.5.803. [DOI] [PubMed] [Google Scholar]
  30. Nakamura H. Electron microscopic study of the prenatal development of the thoracic aorta in the rat. Am J Anat. 1988 Apr;181(4):406–418. doi: 10.1002/aja.1001810409. [DOI] [PubMed] [Google Scholar]
  31. Pachnis V., Belayew A., Tilghman S. M. Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Proc Natl Acad Sci U S A. 1984 Sep;81(17):5523–5527. doi: 10.1073/pnas.81.17.5523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pachnis V., Brannan C. I., Tilghman S. M. The structure and expression of a novel gene activated in early mouse embryogenesis. EMBO J. 1988 Mar;7(3):673–681. doi: 10.1002/j.1460-2075.1988.tb02862.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Parker S. B., Eichele G., Zhang P., Rawls A., Sands A. T., Bradley A., Olson E. N., Harper J. W., Elledge S. J. p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science. 1995 Feb 17;267(5200):1024–1027. doi: 10.1126/science.7863329. [DOI] [PubMed] [Google Scholar]
  34. Poirier F., Chan C. T., Timmons P. M., Robertson E. J., Evans M. J., Rigby P. W. The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time of implantation in the developing embryo. Development. 1991 Dec;113(4):1105–1114. doi: 10.1242/dev.113.4.1105. [DOI] [PubMed] [Google Scholar]
  35. Powell L. M., Wallis S. C., Pease R. J., Edwards Y. H., Knott T. J., Scott J. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell. 1987 Sep 11;50(6):831–840. doi: 10.1016/0092-8674(87)90510-1. [DOI] [PubMed] [Google Scholar]
  36. Sartore S., Scatena M., Chiavegato A., Faggin E., Giuriato L., Pauletto P. Myosin isoform expression in smooth muscle cells during physiological and pathological vascular remodeling. J Vasc Res. 1994 Mar-Apr;31(2):61–81. doi: 10.1159/000159033. [DOI] [PubMed] [Google Scholar]
  37. Schwartz S. M., Campbell G. R., Campbell J. H. Replication of smooth muscle cells in vascular disease. Circ Res. 1986 Apr;58(4):427–444. doi: 10.1161/01.res.58.4.427. [DOI] [PubMed] [Google Scholar]
  38. Steenman M. J., Rainier S., Dobry C. J., Grundy P., Horon I. L., Feinberg A. P. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nat Genet. 1994 Jul;7(3):433–439. doi: 10.1038/ng0794-433. [DOI] [PubMed] [Google Scholar]
  39. Tycko B. Genomic imprinting: mechanism and role in human pathology. Am J Pathol. 1994 Mar;144(3):431–443. [PMC free article] [PubMed] [Google Scholar]
  40. Yoo-Warren H., Pachnis V., Ingram R. S., Tilghman S. M. Two regulatory domains flank the mouse H19 gene. Mol Cell Biol. 1988 Nov;8(11):4707–4715. doi: 10.1128/mcb.8.11.4707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zemel S., Bartolomei M. S., Tilghman S. M. Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2. Nat Genet. 1992 Sep;2(1):61–65. doi: 10.1038/ng0992-61. [DOI] [PubMed] [Google Scholar]
  42. Zhang Y., Tycko B. Monoallelic expression of the human H19 gene. Nat Genet. 1992 Apr;1(1):40–44. doi: 10.1038/ng0492-40. [DOI] [PubMed] [Google Scholar]

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