The association between circulating angiotensin-converting enzyme and cardiovascular risk in the elderly: a cross-sectional study

Abstract

Introduction: A polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with increased risk for cardiovascular disease (CVD). This polymorphism affects the level of circulating ACE, but there is great individual variation, even between those with the same genotype. Few previous studies have investigated the link between circulating ACE and cardiovascular risk. The aim of this study was to investigate this association, and to examine the relationship between ACE level, ACE genotype and CVD.

Materials and methods : The study population consisted of 322 men and 350 women aged 69—87. Plasma ACE level was determined using enzyme-linked immunosorbent assay (ELISA), and ACE genotype was analysed using PCR followed by gel electrophoresis.

Results: In men, ACE levels increased with increasing number of cardiovascular risk factors (p = 0.003). There was a significant association in men between increased ACE level and both diabetes (p = 0.007) and smoking (p = 0.037).

Conclusions:This study shows that cardiovascular risk factors (such as smoking and diabetes) are associated with higher levels of circulating ACE in men. High ACE levels may represent one of the cellular mechanisms involved in producing the vascular damage associated with cardiovascular risk factors.

Keywords

Cardiovascular risk factors diabetes endothelium genetics smoking

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References

Cambien F. , Costerousse O. , Tiret L. , et al. Plasma level and gene polymorphism of angiotensin-converting enzyme in relation to myocardial infarction. Circulation 1994; 90: 669-676.

Rigat B. , Hubert C. , Alhenc-Gelas F. , Cambien F. , Corvol P. and 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 1990; 86: 1343-1346.

Cambien F. , Poirier O. , Lecerf L. , et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641-644.

Mattu RK , Needham EW , Galton DJ , Frangos E. , Clark AJ and Caulfield M. A DNA variant at the angiotensin-converting enzyme gene locus associates with coronary artery disease in the Caerphilly Heart Study. Circulation 1995; 91: 270-274.

Kario K. , Hoshide S. , Umeda Y. , et al. Angiotensinogen and angiotensin-converting enzyme genotypes, and day and night blood pressures in elderly Japanese hypertensives. Hypertens Res 1999; 22: 95-103.

Schunkert H. , Hense HW , Holmer SR , et al. Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy . N Engl J Med 1994; 330: 1634-1638.

Harrap SB , Tzourio C. , Cambien F. , et al. The ACE gene I/D polymorphism is not associated with the blood pressure and cardiovascular benefits of ACE inhibition. Hypertension 2003; 42: 297-303.

Lindpaintner K. , Pfeffer MA , Kreutz R. , et al. A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease. N Engl J Med 1995; 332: 706-711.

Nordestgaard BG , Kontula K. , Benn M. , et al. Effect of ACE insertion/deletion and 12 other polymorphisms on clinical outcomes and response to treatment in the LIFE study. Pharmacogenet Genomics 2010; 20: 77-85.

10.

Sagnella GA , Rothwell MJ , Onipinla AK , Wicks PD , Cook DG and Cappuccio FP A population study of ethnic variations in the angiotensin-converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism. J Hypertens 1999; 17: 657-664.

11.

Bloem LJ , Manatunga AK and Pratt JH Racial difference in the relationship of an angiotensin I-converting enzyme gene polymorphism to serum angiotensin I-converting enzyme activity. Hypertension. 1996; 27: 62-66.

12.

Petrovic D. , Bregar D. , Guzic-Salobir B. , et al. Sex difference in the effect of ACE-DD genotype on the risk of premature myocardial infarction. Angiology 2004; 55: 155-158.

13.

Zhu X. , Bouzekri N. , Southam L. , et al. Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure . Am J Hum Genet 2001; 68: 1139-1148.

14.

Zhu X. , McKenzie CA , Forrester T. , et al. Localization of a small genomic region associated with elevated ACE. Am J Hum Genet. 2000; 67: 1144-1153.

15.

McKenzie CA , Zhu X. , Forrester TE , et al. A genome-wide search replicates evidence of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE) unlinked to the ACE gene. BMC Med Genomics 2008; 1: 23.

16.

Gallagher PE , Li P. , Lenhart JR , Chappell MC and Brosnihan KB Estrogen regulation of angiotensin-converting enzyme mRNA. Hypertension 1999; 33: 323-328.

17.

Saijonmaa O. , Nyman T. , Kosonen R. and Fyhrquist F. Upregulation of angiotensin-converting enzyme by vascular endothelial growth factor. Am J Physiol Heart Circ Physiol 2001; 280: H885-H891.

18.

Hilgenfeldt U. , Puschner T. , Riester U. , Finsterle J. , Hilgenfeldt J. and Ritz E. Low-salt diet downregulates plasma but not tissue kallikrein-kinin system. Am J Physiol 1998; 275: F88-F93.

19.

Ueda S. , Heeley RP , Lees KR , Elliott HL and Connell JM Mistyping of the human angiotensin-converting enzyme gene polymorphism: frequency, causes and possible methods to avoid errors in typing. J Mol Endocrinol 1996; 17: 27-30.

20.

Ljungberg LU and Persson K. Effect of nicotine and nicotine metabolites on Angiotensin-converting enzyme in human endothelial cells. Endothelium. 2008; 15: 239-245.

21.

Gaertner R. , Prunier F. , Philippe M. , Louedec L. , Mercadier JJ and Michel JB Scar and pulmonary expression and shedding of ACE in rat myocardial infarction. Am J Physiol Heart Circ Physiol 2002; 283: H156-H164.

22.

Oppong SY and Hooper NM Characterization of a secretase activity which releases angiotensin-converting enzyme from the membrane. Biochem J 1993; 292: 597-603.

23.

Kleinbongard P. , Dejam A. , Lauer T. , et al. Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 2006; 40: 295-302.

24.

Mizuno K. , Yaginuma K. , Hashimoto S. , Toki T. , Nakamura I. and Fukuchi S. Acute effect of cigarette smoking on serum angiotensin-converting enzyme activity in normal man. Tohoku J Exp Med 1982; 137: 113-114.

25.

Sugiyama Y. , Yotsumoto H. and Takaku F. Increase of serum angiotensin-converting enzyme level after exposure to cigarette smoke and nicotine infusion in dogs. Respiration 1986; 49: 292-295.

26.

Ninomiya Y. , Kioi S. and Arakawa M. Serum angiotensin converting enzyme activity in ex-smokers. Clin Chim Acta 1987; 164: 223-226.

27.

Haboubi NA , Bignell AH and Haboubi NY Serum angiotensin converting enzyme activity in cigarette smokers. Clin Chim Acta 1986; 154: 69-72.

28.

Ng DP , Tai BC , Koh D. , Tan KW and Chia KS Angiotensin-I converting enzyme insertion/deletion polymorphism and its association with diabetic nephropathy: a meta-analysis of studies reported between 1994 and 2004 and comprising 14,727 subjects. Diabetologia 2005; 48: 1008-1016.

29.

Dalla Vestra M. , Simioni N. and Masiero A. Renal effects of dual renin-angiotensin-aldosterone system blockade in patients with diabetic nephropathy. Int Urol Nephrol 2009; 41: 119-126.

30.

Toop MJ , Dallinger KJ , Jennings PE and Barnett AH Angiotensin-converting enzyme (ACE): relationship to insulin-dependent diabetes and microangiopathy. Diabet Med 1986; 3: 455-457.

31.

Van Dyk DJ , Erman A. , Erman T. , Chen-Gal B. , Sulkes J. and Boner G. Increased serum angiotensin converting enzyme activity in type I insulin-dependent diabetes mellitus: its relation to metabolic control and diabetic complications. Eur J Clin Invest 1994; 24: 463-467.

32.

Yusuf S. , Gerstein H. , Hoogwerf B. , et al. Ramipril and the development of diabetes. JAMA 2001; 286: 1882-1885.

33.

Hoeper MM , Tacacs A. , Stellmacher U. and Lichtinghagen R. Lack of association between angiotensin converting enzyme (ACE) genotype, serum ACE activity, and haemodynamics in patients with primary pulmonary hypertension . Heart 2003; 89: 445-446.

34.

Schunkert H. , Hense HW , Muscholl M. , Luchner A. and Riegger GA Association of angiotensin converting enzyme activity and arterial blood pressure in a population-based sample. J Hypertens 1996; 14: 571-575.

35.

Erman A. , Chen-Gal B. , van Dijk DJ , et al. Ovarian angiotensin-converting enzyme activity in humans: relationship to estradiol, age, and uterine pathology. J Clin Endocrinol Metab 1996; 81: 1104-1107.

36.

Dux S. , Aron N. , Boner G. , Carmel A. , Yaron A. and Rosenfeld JB Serum angiotensin converting enzyme activity in normal adults and patients with different types of hypertension. Isr J Med Sci 1984; 20: 1138-1142.

37.

Keavney B. , McKenzie C. , Parish S. , et al. Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators . Lancet 2000; 355: 434-442.