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. 1996 May 15;97(10):2316–2323. doi: 10.1172/JCI118674

Activation of heat shock protein (hsp)70 and proto-oncogene expression by alpha1 adrenergic agonist in rat aorta with age.

J H Chin 1, M Okazaki 1, Z W Hu 1, J W Miller 1, B B Hoffman 1
PMCID: PMC507312  PMID: 8636412

Abstract

Induction of heat shock proteins (hsp) most likely is a homeostatic mechanism in response to metabolic and environmental insults. We have investigated signal transduction mechanisms involved in alpha1, adrenergic receptor stimulation of hsp7O gene expression in isolated aortas with age. We found that alpha1 adrenergic agonists directly induced hsp70 mRNA in rat aorta in vitro; the alpha1, selective antagonist prazosin blocked this effect whereas chloroethylclonidine, an antagonist which has some selectivity for alpha1B receptors, was ineffective. This response was insensitive to pertussis toxin and was partially blocked by the protein kinase C inhibitor H7. Removal of extracellular calcium attenuated induction of hsp70 mRNA but not the induction of c-fos or c-myc. The induction of hsp70 mRNA by either norepinephrine or by phorbol dibutyrate was blunted in aortas from old (24-27 mo) rats whereas c-fos responses were not diminished in the older vessels. The hsp70 response to elevated temperature (42 degrees C) was not changed with age. Activation of hsp70 expression most likely involves a pertussis toxin insensitive G protein which activates protein kinase C, and requires extracellular calcium. With age, hsp70 gene expression induced by stimulation of alpha1 adrenergic receptors is markedly attenuated, which could modify responses to stress or vascular injury with aging.

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Selected References

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  1. Azhar S., Reaven E. Effect of age on cholesterol uptake and utilization by rat adrenals: I. Internalization of lipoprotein-derived cholesteryl esters. Mech Ageing Dev. 1994 Nov 25;77(1):13–25. doi: 10.1016/0047-6374(94)90043-4. [DOI] [PubMed] [Google Scholar]
  2. Becker J., Craig E. A. Heat-shock proteins as molecular chaperones. Eur J Biochem. 1994 Jan 15;219(1-2):11–23. doi: 10.1007/978-3-642-79502-2_2. [DOI] [PubMed] [Google Scholar]
  3. Blake M. J., Buckley D. J., Buckley A. R. Dopaminergic regulation of heat shock protein-70 expression in adrenal gland and aorta. Endocrinology. 1993 Mar;132(3):1063–1070. doi: 10.1210/endo.132.3.8095012. [DOI] [PubMed] [Google Scholar]
  4. Blake M. J., Fargnoli J., Gershon D., Holbrook N. J. Concomitant decline in heat-induced hyperthermia and HSP70 mRNA expression in aged rats. Am J Physiol. 1991 Apr;260(4 Pt 2):R663–R667. doi: 10.1152/ajpregu.1991.260.4.R663. [DOI] [PubMed] [Google Scholar]
  5. Blake M. J., Klevay L. M., Halas E. S., Bode A. M. Blood pressure and heat shock protein expression in response to acute and chronic stress. Hypertension. 1995 Apr;25(4 Pt 1):539–544. doi: 10.1161/01.hyp.25.4.539. [DOI] [PubMed] [Google Scholar]
  6. Blake M. J., Udelsman R., Feulner G. J., Norton D. D., Holbrook N. J. Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9873–9877. doi: 10.1073/pnas.88.21.9873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chang N. T., Huang L. E., Liu A. Y. Okadaic acid markedly potentiates the heat-induced hsp 70 promoter activity. J Biol Chem. 1993 Jan 15;268(2):1436–1439. [PubMed] [Google Scholar]
  8. Choi H. S., Lin Z., Li B. S., Liu A. Y. Age-dependent decrease in the heat-inducible DNA sequence-specific binding activity in human diploid fibroblasts. J Biol Chem. 1990 Oct 15;265(29):18005–18011. [PubMed] [Google Scholar]
  9. Cizza G., Pacak K., Kvetnansky R., Palkovits M., Goldstein D. S., Brady L. S., Fukuhara K., Bergamini E., Kopin I. J., Blackman M. R. Decreased stress responsivity of central and peripheral catecholaminergic systems in aged 344/N Fischer rats. J Clin Invest. 1995 Mar;95(3):1217–1224. doi: 10.1172/JCI117771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cotecchia S., Schwinn D. A., Randall R. R., Lefkowitz R. J., Caron M. G., Kobilka B. K. Molecular cloning and expression of the cDNA for the hamster alpha 1-adrenergic receptor. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7159–7163. doi: 10.1073/pnas.85.19.7159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Deguchi Y., Negoro S., Kishimoto S. Age-related changes of heat shock protein gene transcription in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 1988 Dec 15;157(2):580–584. doi: 10.1016/s0006-291x(88)80289-4. [DOI] [PubMed] [Google Scholar]
  12. Fargnoli J., Kunisada T., Fornace A. J., Jr, Schneider E. L., Holbrook N. J. Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc Natl Acad Sci U S A. 1990 Jan;87(2):846–850. doi: 10.1073/pnas.87.2.846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fawcett T. W., Sylvester S. L., Sarge K. D., Morimoto R. I., Holbrook N. J. Effects of neurohormonal stress and aging on the activation of mammalian heat shock factor 1. J Biol Chem. 1994 Dec 23;269(51):32272–32278. [PubMed] [Google Scholar]
  14. Heydari A. R., Takahashi R., Gutsmann A., You S., Richardson A. Hsp70 and aging. Experientia. 1994 Nov 30;50(11-12):1092–1098. doi: 10.1007/BF01923466. [DOI] [PubMed] [Google Scholar]
  15. Heydari A. R., Wu B., Takahashi R., Strong R., Richardson A. Expression of heat shock protein 70 is altered by age and diet at the level of transcription. Mol Cell Biol. 1993 May;13(5):2909–2918. doi: 10.1128/mcb.13.5.2909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hieble J. P., Bylund D. B., Clarke D. E., Eikenburg D. C., Langer S. Z., Lefkowitz R. J., Minneman K. P., Ruffolo R. R., Jr International Union of Pharmacology. X. Recommendation for nomenclature of alpha 1-adrenoceptors: consensus update. Pharmacol Rev. 1995 Jun;47(2):267–270. [PubMed] [Google Scholar]
  17. Huang L. E., Zhang H., Bae S. W., Liu A. Y. Thiol reducing reagents inhibit the heat shock response. Involvement of a redox mechanism in the heat shock signal transduction pathway. J Biol Chem. 1994 Dec 2;269(48):30718–30725. [PubMed] [Google Scholar]
  18. Kim D., Ouyang H., Li G. C. Heat shock protein hsp70 accelerates the recovery of heat-shocked mammalian cells through its modulation of heat shock transcription factor HSF1. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2126–2130. doi: 10.1073/pnas.92.6.2126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Koizumi T., Negishi M., Ichikawa A. Activation of heat shock transcription factors by delta 12-prostaglandin J2 and its inhibition by intracellular glutathione. Biochem Pharmacol. 1993 Jun 22;45(12):2457–2464. doi: 10.1016/0006-2952(93)90227-n. [DOI] [PubMed] [Google Scholar]
  20. Lee Y. J., Berns C. M., Erdos G., Corry P. M. Effect of isoquinolinesulfonamides on heat shock gene expression during heating at 41 degrees C in human carcinoma cell lines. Biochem Biophys Res Commun. 1994 Mar 15;199(2):714–719. doi: 10.1006/bbrc.1994.1287. [DOI] [PubMed] [Google Scholar]
  21. Leprêtre N., Mironneau J., Morel J. L. Both alpha 1A- and alpha 2A-adrenoreceptor subtypes stimulate voltage-operated L-type calcium channels in rat portal vein myocytes. Evidence for two distinct transduction pathways. J Biol Chem. 1994 Nov 25;269(47):29546–29552. [PubMed] [Google Scholar]
  22. Lis J., Wu C. Protein traffic on the heat shock promoter: parking, stalling, and trucking along. Cell. 1993 Jul 16;74(1):1–4. doi: 10.1016/0092-8674(93)90286-y. [DOI] [PubMed] [Google Scholar]
  23. Liu A. Y., Lin Z., Choi H. S., Sorhage F., Li B. Attenuated induction of heat shock gene expression in aging diploid fibroblasts. J Biol Chem. 1989 Jul 15;264(20):12037–12045. [PubMed] [Google Scholar]
  24. Liu Q. Y., Karpinski E., Pang P. K. L-channel modulation by alpha-1 adrenoceptor activation in neonatal rat ventricular cells: intracellular mechanisms. J Pharmacol Exp Ther. 1994 Nov;271(2):944–951. [PubMed] [Google Scholar]
  25. Lomasney J. W., Cotecchia S., Lorenz W., Leung W. Y., Schwinn D. A., Yang-Feng T. L., Brownstein M., Lefkowitz R. J., Caron M. G. Molecular cloning and expression of the cDNA for the alpha 1A-adrenergic receptor. The gene for which is located on human chromosome 5. J Biol Chem. 1991 Apr 5;266(10):6365–6369. [PubMed] [Google Scholar]
  26. Minowada G., Welch W. J. Clinical implications of the stress response. J Clin Invest. 1995 Jan;95(1):3–12. doi: 10.1172/JCI117655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mivechi N. F., Murai T., Hahn G. M. Inhibitors of tyrosine and Ser/Thr phosphatases modulate the heat shock response. J Cell Biochem. 1994 Feb;54(2):186–197. doi: 10.1002/jcb.240540207. [DOI] [PubMed] [Google Scholar]
  28. Morimoto R. I. Cells in stress: transcriptional activation of heat shock genes. Science. 1993 Mar 5;259(5100):1409–1410. doi: 10.1126/science.8451637. [DOI] [PubMed] [Google Scholar]
  29. Morimoto R. I., Sarge K. D., Abravaya K. Transcriptional regulation of heat shock genes. A paradigm for inducible genomic responses. J Biol Chem. 1992 Nov 5;267(31):21987–21990. [PubMed] [Google Scholar]
  30. Mosser D. D., Kotzbauer P. T., Sarge K. D., Morimoto R. I. In vitro activation of heat shock transcription factor DNA-binding by calcium and biochemical conditions that affect protein conformation. Proc Natl Acad Sci U S A. 1990 May;87(10):3748–3752. doi: 10.1073/pnas.87.10.3748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nitta Y., Abe K., Aoki M., Ohno I., Isoyama S. Diminished heat shock protein 70 mRNA induction in aged rat hearts after ischemia. Am J Physiol. 1994 Nov;267(5 Pt 2):H1795–H1803. doi: 10.1152/ajpheart.1994.267.5.H1795. [DOI] [PubMed] [Google Scholar]
  32. Okazaki M., Hu Z. W., Fujinaga M., Hoffman B. B. Alpha 1 adrenergic receptor-induced c-fos gene expression in rat aorta and cultured vascular smooth muscle cells. J Clin Invest. 1994 Jul;94(1):210–218. doi: 10.1172/JCI117309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Perez D. M., Piascik M. T., Graham R. M. Solution-phase library screening for the identification of rare clones: isolation of an alpha 1D-adrenergic receptor cDNA. Mol Pharmacol. 1991 Dec;40(6):876–883. [PubMed] [Google Scholar]
  34. Piascik M. T., Smith M. S., Soltis E. E., Perez D. M. Identification of the mRNA for the novel alpha 1D-adrenoceptor and two other alpha 1-adrenoceptors in vascular smooth muscle. Mol Pharmacol. 1994 Jul;46(1):30–40. [PubMed] [Google Scholar]
  35. Price D. T., Schwinn D. A., Lomasney J. W., Allen L. F., Caron M. G., Lefkowitz R. J. Identification, quantification, and localization of mRNA for three distinct alpha 1 adrenergic receptor subtypes in human prostate. J Urol. 1993 Aug;150(2 Pt 1):546–551. doi: 10.1016/s0022-5347(17)35544-1. [DOI] [PubMed] [Google Scholar]
  36. Rokosh D. G., Bailey B. A., Stewart A. F., Karns L. R., Long C. S., Simpson P. C. Distribution of alpha 1C-adrenergic receptor mRNA in adult rat tissues by RNase protection assay and comparison with alpha 1B and alpha 1D. Biochem Biophys Res Commun. 1994 May 16;200(3):1177–1184. doi: 10.1006/bbrc.1994.1575. [DOI] [PubMed] [Google Scholar]
  37. Schwinn D. A., Johnston G. I., Page S. O., Mosley M. J., Wilson K. H., Worman N. P., Campbell S., Fidock M. D., Furness L. M., Parry-Smith D. J. Cloning and pharmacological characterization of human alpha-1 adrenergic receptors: sequence corrections and direct comparison with other species homologues. J Pharmacol Exp Ther. 1995 Jan;272(1):134–142. [PubMed] [Google Scholar]
  38. Schwinn D. A., Lomasney J. W., Lorenz W., Szklut P. J., Fremeau R. T., Jr, Yang-Feng T. L., Caron M. G., Lefkowitz R. J., Cotecchia S. Molecular cloning and expression of the cDNA for a novel alpha 1-adrenergic receptor subtype. J Biol Chem. 1990 May 15;265(14):8183–8189. [PubMed] [Google Scholar]
  39. Stevenson M. A., Calderwood S. K. Members of the 70-kilodalton heat shock protein family contain a highly conserved calmodulin-binding domain. Mol Cell Biol. 1990 Mar;10(3):1234–1238. doi: 10.1128/mcb.10.3.1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Udelsman R., Blake M. J., Stagg C. A., Li D. G., Putney D. J., Holbrook N. J. Vascular heat shock protein expression in response to stress. Endocrine and autonomic regulation of this age-dependent response. J Clin Invest. 1993 Feb;91(2):465–473. doi: 10.1172/JCI116224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Udelsman R., Li D. G., Stagg C. A., Gordon C. B., Kvetnansky R. Adrenergic regulation of adrenal and aortic heat shock protein. Surgery. 1994 Aug;116(2):177–182. [PubMed] [Google Scholar]
  42. Wu D., Katz A., Lee C. H., Simon M. I. Activation of phospholipase C by alpha 1-adrenergic receptors is mediated by the alpha subunits of Gq family. J Biol Chem. 1992 Dec 25;267(36):25798–25802. [PubMed] [Google Scholar]
  43. Yamamoto N., Smith M. W., Maki A., Berezesky I. K., Trump B. F. Role of cytosolic Ca2+ and protein kinases in the induction of the hsp70 gene. Kidney Int. 1994 Apr;45(4):1093–1104. doi: 10.1038/ki.1994.146. [DOI] [PubMed] [Google Scholar]

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