Subscribe to RSS
DOI: 10.1055/s-2006-951307
© Georg Thieme Verlag KG Stuttgart · New York
Insertion/Deletion Polymorphism on ACE Gene is Associated with Endothelial Dysfunction in Young Patients with Hypertension
Publication History
Received 31 January 2006
Accepted after revision 29 May 2006
Publication Date:
18 September 2006 (online)
Abstract
Endothelial dysfunction, insulin resistance (IR) and genetic predispositions are important risk factors of hypertension. Aim of our study was to test the hypothesis, whether insertion/deletion (I/D) polymorphism on the angiotensin converting enzyme (ACE) gene and M235T polymorphism on angiotesinogen gene (AGT) correlates with parameters of insulin sensitivity and plasminogen activator inhibitor (PAI-1) levels in newly diagnosed hypertensive patients as compared with normotensive controls. Blood pressure (BP), fasting plasma glucose, insulin, epinephrine, norepinephrine and PAI-1 concentrations were determined in 30 male patients with hypertension grade 1 (HT) and in 31 matched healthy subjects (NT). Insulin resistance was estimated using IR HOMA formula. Patients with HT had increased levels of PAI-1, norepinephrine, fasting plasma insulin levels, IR HOMA (p<0.001) compared to controls. Subjects (HT and NT) with DD and ID genotype had a significantly higher systolic BP (p<0.05) and PAI-1 compared to those with II genotype. Homozygous subjects 235T had a higher systolic BP and higher levels of epinephrine and norepinephrine than heterozygous or homozygous M235 (p<0.05). In conclusion, no association was found between M235T polymorphism and insulin resistance or PAI-1 levels, but results indicate relationship between I/D polymorphism of the ACE gene and plasma PAI-1 levels in the early stage of hypertension.
Key words
Blood pressure - insertion/deletion (I/D) polymorphism - angiotensin converting enzyme (ACE) - hypertension - PAI-1
References
- 1 Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM. et al . Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992; 71 169-180
- 2 Horan MJ, Lenfant C. Epidemiology of blood pressure and predictors of hypertension. Hypertension. 1990; 15 ((2 Suppl)) I20-I24
- 3 Perry IJ, Whincup PH, Shaper AG. Environmental factors in the development of essential hypertension. Br Med Bull. 1994; 50 246-259
- 4 Schjoedt KJ, Jacobsen P, Rossing K, Boomsma F, Parving HH. Dual blockade of the renin- angiotensin-aldosterone system in diabetic nephropathy: the role of aldosterone. Horm Metab Res. 2005; 37 ((Suppl 1)) 4-8
- 5 Walker WG, Whelton PK, Saito H, Russell RP, Hermann J. Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects. Hypertension. 1979; 1 287-291
- 6 Krizanova O, Obdrzalkova D, Polakova H, Jelok I, Hudecova S. Molecular variants of the renin-angiotensin system components in the Slovak population. Physiol Res. 1997; 46 357-361
- 7 Rotimi C, Morrison L, Cooper R, Oyejide C, Effiong E, Ladipo M. Angiotensinogen gene in human hypertension: lack of an association of the 235 T allele among African Americans. Hypertension. 1994; 24 591-594
- 8 Sethi AA, Nordestgaard BG, Tybjaerg-Hansen A. Angiotensinogen gene polymorphism, plasma angiotensinogen, and risk of hypertension and ischemic heart disease: a meta-analysis. Arterioscler Thromb Vasc Biol. 2003; 23 1269-1275
- 9 Ueda S, Elliott HL, Morton JJ, Connel JMC. Enhanced pressor response to angiotensin I in normotensive men with the ACE deletion allele. Hypertension. 1995; 25 1266-1269
- 10 Soubrier F, Wei L, Hubert C, Clauser E, Alhens-Gelas F, Corvol P. Molecular biology of the angiotensin I converting enzyme. II. Structure-function. Gene polymorphism and clinical implications. J Hypertens. 1993; 11 599-604
- 11 Mendonca I, Freitas IA, Sousa CA, Gomes S, Faria P, Drumond A, Silva G, Araujo JJ, Freitas S, Ornelas I, Andrade G, Coelho AP, Silva PM, Cardoso A, Brehm AA, dos Reis RP. Polymorphism of the ACE gene is associated with extent and severity of coronary disease. Rev Port Cardiol. 2004; 23 1605-1611
- 12 Takahashi K, Nakamura H, Kubota I, Takahashi N, Tomoike H. Association of ACE gene polymorphisms with coronary artery disease in a northern area of Japan. Jpn Heart J. 1995; 36 557-564
- 13 Cambien F, Poirier O, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Bard JM, Bara L, Ricard S. et al . Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992; 359 641-644
- 14 Evans AE, Poirier O, Kee F Lecerf L, McCrum E, Falconer T, Crane J, O'Rourke DF, Cambien F. Polymorphism of the angiotensin-converting enzyme gene in subjects who die from coronary heart disease. Q J Med. 1994; 87 211-214
- 15 Makris TK, Tsoukala C, Krespi P, Hatzizacharias A, Gialeraki A, Papargyriou J, Votteas V, Mandalaki T. Haemostasis balance disorders in patients with essential hypertension. Thromb Res. 1997; 88 99-107
- 16 Junker R, Heinrich J, Schulte H, Erren M, Assmann G. Hemostasis in normotensive and hypertensive men: results of the PROCAM study. The prospective cardiovascular Munster study. J Hypertens. 1998; 16 917-923
- 17 Oliver JJ, Webb DJ, Newby DE. Stimulated tissue plasminogen activator release as a marker of endothelial function in humans. Arterioscler Thromb Vasc Biol. 2005; 25 2470-2479
- 18 Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation. 1993; 87 1969-1973
- 19 Feener EP, Northrup JM, Aiello LP, King GL. Angiotensin II induces plasminogen activator inhibitor-1 and -2 expressions in vascular endothelial and smooth muscle cells. J Clin Invest. 1995; 95 1353-1362
- 20 Makris TK, Stavroulakis GA, Dafni UG, Gialeraki AE, Krespi PG, Hatzizacharias AN, Tsoukala CG, Vythoulkas JS, Kyriakidis MK. ACE/DD genotype is associated with hemostasis balance disturbances reflecting hypercoagulability and endothelial dysfunction in patients with untreated hypertension. Am Heart J. 2000; 140 760-765
- 21 Pankow JS, Arnett DK, Borecki IB, Hunt SC, Eckfeldt JH, Folsom AR, Djousse L. Lack of association between the angiotensin-converting enzyme insertion/deletion polymorphism and plasminogen activator inhibitor-1 antigen levels in the National Heart, Lung, and Blood Institute Family Heart Study. Blood Coagul Fibrinolysis. 2000; 11 551-558
- 22 Jeng JR, Harn HJ, Yueh KC, Jeng CY, Shieh SM. Plasminogen activator inhibitor-1 and angiotensin I converting enzyme gene polymorphism in patients with hypertension. Am J Hypertens. 1998; 11 235-239
- 23 Panahloo A, Andres C, Mohamed-Ali V, Gould MM, Talmud P, Humphries SE, Yudkin JS. The insertion allele of the ACE gene I/D polymorphism. A candidate gene for insulin resistance?. Circulation. 1995; 92 3390-3393
- 24 Perticone F, Ceravolo R, Iacopino S, Cloro C, Ventura G, Maio R, Gulletta E, Perrotti N, Mattioli PL. Relationship between angiotensin-converting enzyme gene polymorphism and insulin resistance in never-treated hypertensive patients. J Clin Endocrinol Metab. 2001; 86 172-178
- 25 Ceravolo R, Maio R, Cuda G, Scozzafava A, Sciacqua A, Vatrano M, Bellieni G, D'Angelo G, Schipani FA, Sesti G, Perticone F. Relation of fasting insulin related to insertion/deletion polymorphism of angiotensin-converting enzyme-gene and cardiac mass in never-treated patients with systemic hypertension. Am J Cardiol. 2003; 92 1234-1237
- 26 Mondry A, Loh M, Liu P, Zhu AL, Nagel M. Polymorphisms of the insertion/deletion ACE and M235T AGT genes and hypertension: surprising new findings and meta-analysis of data. BMC Nephrol. 2005; 6 1
- 27 Sheu WH, Lee WJ, Jeng CY, Young MS, Ding YA, Chen YT. Angiotensinogen gene polymorphism is associated with insulin resistance in nondiabetic men with or without coronary heart disease. Am Heart J. 1998; 136 125-131
- 28 ESH/ECS 2003 - European Society of Hypetension . European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003; 21 1011-1053
- 29 Friedewald WT, Levy RI, Fredrickson DS. Estimation of concentration of low- density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18 499-502
- 30 Peuler JD, Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma noepinephrin, epinephrine and dopamine. Life Sci. 1977; 21 625-636
- 31 Matthews Dr, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28 412-419
- 32 Russ AP, Maerz W, Ruzicka V, Stein U, Gross W. Rapid detection of the hypertension-associated Met235 → Thr allele of the human angiotensinogen gene. Hum Mol Genet. 1993; 2 609-610
- 33 Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1992; 86 1343-1346
- 34 Jamerson KA, Julius S, Gudbrandsson T, Andrersson O, Brant DO. Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension. 1993; 21 618-623
- 35 Julius S, Jamerson K. Sympathetics, insulin resistance and coronary risk in hypertension: the ‘chicken-and-egg’ question. J Hypertens. 1994; 12 495-502
- 36 Celentano A, Mancini FP, Crivaro M, Palmieri V, de Stefano V, Ferrere LA, Di Minno G, de Simone G. Influence of cardiovascular risk factors on relation between angiotensin converting enzyme-gene polymorphism and blood pressure in arterial hypertension. J Hypertens. 1998; 16 985-991
- 37 Martin LJ, Woo JG, Daniels SR, Goodman E, Dolan LM. The Relationships of Adiponectin with Insulin and Lipids Are Strengthened with Increasing Adiposity. J Clin Endocrinol Metab. 2005; 90 4255-4259
- 38 Janan-Delene B, Chagnaud C, Raccah D, Alessi MC, Juhan-Vague I, Vague P. Visceral fat as a main determinant of plasminogen activator inhibitor-1 in women. Int J Obes. 1998; 22 312-317
- 39 Ferrannini E, Buzzigoli G, Bonadonna R, Ciociaro D, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987; 317 350-357
- 40 Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities. The role of insulin resistance and the sympathoadrenal system. N Engl J Med. 1996; 334 374-381
- 41 Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese men. J Clin Invest. 1990; 85 1844-1852
- 42 Freedman BI, Rich SS, Sale MM, Heiss G, Djousse L, Pankow JS, Province MA, Rao DC, Lewis CE, Chen YD, Beck SR. HyperGEN Investigators. Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families. Diabetologia. 2005; 48 661-668
- 43 Vitale C, Mercuro G, Castiglioni C, Cornoldi A, Tulli A, Fini M, Volterrani M, Rosano GM. Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome. Cardiovasc Diabetol. 2005; 4 6
- 44 Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, Bonadonna RC. Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation. 2002; 105 576-582
- 45 Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. Endocrinol Metab Clin North Am. 2005; 34 49-62
Correspondence
Adela PenesovaM.D.
Institute of Experimental Endocrinology·Slovak Academy of Sciences
Vlarska 3·833 06 Bratislava·Slovakia
Phone: +421/2/54 77 49 42
Fax: +421/2/54 77 42 47
Email: Adela.Penesova@savba.sk