Abstract
Microangiopathy-related cerebral damage (MARCD) is a common finding in the elderly. It may lead to cognitive impairment and gait disturbances. Arterial hypertension and age are the best accepted risk factors for MARCD. Genes involved in blood pressure regulation, like genes encoding the proteins of the renin-angiotensin system (RAS) therefore represents good candidate genes for MARCD. Plasma angiotensinogen level is a major determinant of the RAS activity. Positive correlation between angiotensinogen gene expression and RAS activity, as well as blood pressure were observed. Common mutations described in the AGT promoter were able to alter AGT expression in cell culture. We described that 4 frequent mutations at the AGT promoter are combined in 5 haplotypes coded as A (−6:g, −20:a,−152:g, −217:g), B (−6:a, −20:c, −152:g, −217:g), C (−6:a, −20:c, −152:a, −217:g), D (−6:a, −20:a, −152:g, −217:g), and E (−6:a, −20:a, −152:g, −217:a). The B haplotype was significantly associated with MARCD in the cohort of the Austrian Stroke Prevention Study (p = 0.005). The association was independent of hypertension, which pinpointed to a possible role of the local RAS in this relationship. Investigation of the promoter activity of the AGT gene in astrocytes suggests that expression of this gene may be modulated by the haplotype.
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References
Awad LA, Johnson PC, Spetzler RF, Hodak JA (1986) Incidental subcortical lesions identified on magnetic resonance imaging in the elderly. II. Postmorte histopatho-logical correlations. Stroke 17: 1090–1097
Bots ML, van Swieten JC, Breteler MMB, de Jong PTVM, van Gijn J, Hofman A, Grobbee DE (1993) Cerebral white matter lesions and atherosclerosis in the Rotterdam study. Lancet 341: 1232–1237
Bunnemann B, Fuxe K, Ganten D (1992)The brain renin-angiotens system: localisation and general significance. J Cardiovasc Pharmacol 19[5uppl 6]: S51–S62
Carmelli D, DeCarli C, Swan G, Jack LM, Reed T, Wolf PA, Miller BL (1998) Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 29: 1177–1181
Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Radner H, Lechner H (1993) Pathologic correlates of incidental white matter signal hyper-intensities.Neurology 43:1683–1689
Ford CM, LiS, Pickering JG (1999) AngiotensinIIstimulatescollagensynthesisinhuman vascular smooth muscle cells. Involvement of the AT(I) receptor, transforming growth factor-beta, and tyrosine phosphorylation. Arterioscler Thromb Vasc Bioi 19:1843–1851
Fukai T, Siegfried MR, Ushio-Fukai M, Grie KK, Harrison DG (1999) Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension. Circ Res 85: 23–28
Fukamizu A, Takahashi S, Seo MS, Tada M, Tanimoto K, Uehara S, Murakami K (1990) Structure and expression of the human angiotensin gene. J Bioi Chern 265: 7576–7582
Haberl RL, Anneser F, Villringer A, Einhaupl KM (1990) Angiotensin II induces endot-helium dependent vasodilation of rat cerebral arterioles. Am J Physiol 258: H1840–1846
Haberl RL, Decker-Hermann PJ, Hermann K (1996) Effect of renin on brain arterioles and cerebral blood flow in rabbits. J Cereb Blood Flow Metab 16: 714–719
Inoue I, Nakajima T, Williams CS, Quackenbush J, Puryear R, Powers M, Cheng T, Ludwig EH, Sharma AM, Hata A, Jaunemaitre X, Lalouel JM (1997) A nucleotide ubstitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J Clin Invest 99: 1786–1797
Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM (1992) Molecular basis of human hypertension: role of angiotensinogen. Cell 71(1): 169–180
Kakinuma Y, Hama H, Sugiyama F, Yagami K, Goto K, Murakami K, Fukamizu A (1998) Impaired blood-brain barrier function in angiotensinogen deficient mice. Nat Med 4: 1078–1080
Kim HS, Krege JR, Kluckman KD, Hagaman JR, Hodgin JB, Best CF, Jenette JC, Coffman TM, Maeda N, Smithies O (1995) Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA 92: 2735–2739
Lynch KR, Peach MJ (1991) Molecular biology of angiotensinogen. ypertension17:263–269
Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk Be, Delafontaine P, Bernstein KE (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II ATlreceptor. Nature 375: 247–250
Morgan T, Craven C, Nelson L, Lalouel JM, Ward K (1997) Angiotensinogen T235 expression is elevated in decidual spiral arteries. J Clin Invest 100: 1406–1415
Pantoni L, Garcia JR (1995) The significance of cerebral white matter abnormalities 100 years after Binswanger’s report. A review. Stroke 26: 1293–1301
Paul M, Wagner J, Dzau VJ (1993) Gene expression of the renin-angiotensin system in human tissues. J Clin Invest 91: 2058–2064
Rajagopalan S, Kurz S, Miinzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG (1996) Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADHINADPH oxidase activation. J Clin Invest 97:1916–1923
Schmidt H, Fazekas F, Kostner GM, Schmidt R (2000) Genetic aspects of microangiopathy-related cerebral damage. J Neural Transm [Suppl] 59: 15–21
Schmidt H, Fazekas F, Kostner GM, van Duijn CM, Schmidt R (2001) Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage. Results of the Austrian Stroke Prevention Study. Stroke 32: 405–412
Schmidt R, Fazekas F, Hayn M, Schmidt H, Kapeller P, Roob G, Offenbacher H, Schumacher M, Eber B, Weinrauch V, Kostner GM, Esterbauer H (1997) Risk factors for microangiopathy-related cerebral damage in the Austrian Stroke Prevention Study. J Neurol Sci 152: 15–21
Schmidt R, Schmidt H, Fazekas F, Launer LJ, Niederkorn K, Kapeller P, Lechner A, Kostner GM (2001) Angiotensinogen polymorphism M235T, carotid atherosclerosis,and small vessel disease-related cerebral abnormalities. Hypertension 38: 110–115
Taubman MB, Berk BC, Izumo S, Tsuda T, Alexander RW, Nadal-Ginard B (1989) Angiotensin II induces c-fos mRNA in aortic smooth muscle. J Bioi Chern 264: 526–530
Ushio-Fukai M, Alexander RW, Akers M, Griendling KK (1998) p38 Mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. J Bioi Chern 273: 15022–15029
Van Swieten JC, Van den Hout JHW, Van Ketel BA, Hijdra A, Wokke JHJ, Van Gijn J (1991a). Periventricular lesions in the white on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain 114: 761–774
Van Swieten JC, Geykes GG, Derix MMA, Peeck BM, Ramos LMP, van Latum JC, van Gijn J (1991b) Hypertension in the elderly is associated with white matter lesions and cognitive decline. Ann Neurol 30: 825–830
Weber H, Taylor SD, Molloy CJ (1994) Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. J Clin Invest 93: 788–798
Wei AP, Kontos HA, Patterson JL (1978) Vasoconstrictor effect of angiotensin on pial arteries. Stroke 9: 487–489
Whalley ET, Wa WM (1988) Cerebrovascular reactivity to angiotensin and angiotensin-converting enzyme activity in cerebrospinal fluid. Brain Res 438: 1–7
Wright JW, Harding JW (1992) Regulatory role of brain angiotensinogens in the control of physiological and behavioral responses. Brain Res Rev 17: 227–262
Yanai K, Nibu Y, Murakami K, Fukamizu A (1996) A cis-Acting DNA Element located between TATA box and transcription initiation site is critical in response to regulatory sequences in human angiotensinogen gene. J Bioi Chern 271: 15981–15986
Yanai K, Matsuyama S, Murakami K, Fukamizu A (1997) Differential action of AGCEF2 upon cell type-dependent expression of human angiotensinogen gene. FEBS Lett 412: 285–289
Yanai K, Saito T, Hirota K, Kobayashi H, Murakami K, Fukamizu A (1997) Molecular variation of the human angiotensinogen core promoter element located between the TATA box and transcription initiation site affects its transcriptional activity. J Bioi Chern 272(48): 30558–30562
Yang G, Merril DC, Thompson MW, Robillard JE, Sigmund CD (1994) Functional expression of the human angiotensinogen gene in transgenic mice. J Bioi Chern 269: 32497–32502
Zhao YY, Zhou J, Narayanan CS, Cui Y, Kumar A (1999) Role of CIA polymorphism at-20 on the expression of human angiotensinogen gene. Hypertension 33: 108–115
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Schmidt, H., Fazekas, F., Schmidt, R. (2002). Microangiopathy-related cerebral damage and angiotensinogen gene: from epidemiology to biology. In: Jellinger, K.A., Schmidt, R., Windisch, M. (eds) Ageing and Dementia Current and Future Concepts. Journal of Neural Transmission. Supplementa, vol 62. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6139-5_5
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DOI: https://doi.org/10.1007/978-3-7091-6139-5_5
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