Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy

BMC Cardiovascular Disorders

Hakan Melhus¹  Ann-Christine Syvänen¹  Ulrika Liljedahl¹  Fredrik Nyström⁴  Karl Peter Öhman⁶  Karin Malmqvist³  Thomas Kahan³  Lisa Kurland¹  Karl Michaëlsson⁵  Lars Lind²  Par Hallberg¹ 

[1] Department of Medical Sciences, Uppsala University, Uppsala, Sweden;AstraZeneca Research & Development, Mölndal, Sweden;Division of Internal Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden;Department of Biomedicine and Surgery, Faculty of Health Sciences, Linköping, Sweden;Department of Surgical Sciences, Uppsala University, Uppsala, Sweden;Department of Medicine and Care, Faculty of Health Sciences, Linköping, Sweden

关键词: bradykinin.;    pharmacogenomics;    angiotensin;    left ventricular hypertrophy;    polymorphism;    hypertension;    irbesartan;    Aminopeptidase;   

Others  :  1088610
DOI  :  10.1186/1471-2261-3-11

 received in 2003-07-15, accepted in 2003-09-18,  发布年份 2003

【 摘 要 】

Background

Adipocyte-derived leucine aminopeptidase (ALAP) is a recently identified member of the M1 family of zinc-metallopeptidases and is thought to play a role in blood pressure control through inactivation of angiotensin II and/or generation of bradykinin. The enzyme seems to be particularly abundant in the heart. Recently, the Arg528-encoding allele of the ALAP gene was shown to be associated with essential hypertension.

Methods

We evaluated the influence of this polymorphism on the change in left ventricular mass index in 90 patients with essential hypertension and echocardiographically diagnosed left ventricular hypertrophy, randomised in a double-blind study to receive treatment with either the angiotensin II type I receptor antagonist irbesartan or the beta₁-adrenoceptor blocker atenolol for 48 weeks. Genyotyping was performed using minisequencing.

Results

After adjustment for potential covariates (blood pressure and left ventricular mass index at baseline, blood pressure change, age, sex, dose and added antihypertensive treatment), there was a marked difference between the Arg/Arg and Lys/Arg genotypes in patients treated with irbesartan; those with the Arg/Arg genotype responded on average with an almost two-fold greater regression of left ventricular mass index than patients with the Lys/Arg genotype (-30.1 g/m² [3.6] vs -16.7 [4.5], p = 0.03).

Conclusions

The ALAP genotype seems to determine the degree of regression of left ventricular hypertrophy during antihypertensive treatment with the angiotensin II type I receptor antagonist irbesartan in patients with essential hypertension and left ventricular hypertrophy. This is the first report of a role for ALAP/aminopeptidases in left ventricular mass regulation, and suggests a new potential target for antihypertensive drugs.

【 授权许可】

   
2003 Hallberg et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH: Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991, 114:345-352.
• [2]Schillaci G, Verdecchia P, Porcellati C, Cuccurullo O, Cosco C, Perticone F: Continuous relation between left ventricular mass and cardiovascular risk in essential hypertension. Hypertension 2000, 35:580-586.
• [3]Verdecchia P, Carini G, Circo A, Dovellini E, Giovannini E, Lombardo M, Solinas P, Gorini M, Maggioni AP: Left ventricular mass and cardiovascular morbidity in essential hypertension: the MAVI study. J Am Coll Cardiol 2001, 38:1829-1835.
• [4]Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990, 322:1561-1566.
• [5]Unger T: The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002, 89:3A-9A; discussion 10A.
• [6]Zuraw B: Bradykinin in protection against left-ventricular hypertrophy. Lancet 2001, 358:1116-1118.
• [7]Taylor A: Aminopeptidases: structure and function. Faseb J 1993, 7:290-298.
• [8]Healy DP, Song L: Kidney aminopeptidase A and hypertension, part I: spontaneously hypertensive rats. Hypertension 1999, 33:740-745.
• [9]Song L, Healy DP: Kidney aminopeptidase A and hypertension, part II: effects of angiotensin II. Hypertension 1999, 33:746-752.
• [10]Hattori A, Kitatani K, Matsumoto H, Miyazawa S, Rogi T, Tsuruoka N, Mizutani S, Natori Y, Tsujimoto M: Characterization of recombinant human adipocyte-derived leucine aminopeptidase expressed in Chinese hamster ovary cells. J Biochem (Tokyo) 2000, 128:755-762.
• [11]Matsumoto H, Rogi T, Yamashiro K, Kodama S, Tsuruoka N, Hattori A, Takio K, Mizutani S, Tsujimoto M: Characterization of a recombinant soluble form of human placental leucine aminopeptidase/oxytocinase expressed in Chinese hamster ovary cells. Eur J Biochem 2000, 267:46-52.
• [12]Hattori A, Matsumoto H, Mizutani S, Tsujimoto M: Molecular cloning of adipocyte-derived leucine aminopeptidase highly related to placental leucine aminopeptidase/oxytocinase. J Biochem (Tokyo) 1999, 125:931-938.
• [13]Yamamoto N, Nakayama J, Yamakawa-Kobayashi K, Hamaguchi H, Miyazaki R, Arinami T: Identification of 33 polymorphisms in the adipocyte-derived leucine aminopeptidase (ALAP) gene and possible association with hypertension. Hum Mutat 2002, 19:251-257.
• [14]Malmqvist K, Kahan T, Edner M, Held C, Hagg A, Lind L, Muller-Brunotte R, Nystrom F, Ohman KP, Osbakken MD, Ostergern J: Regression of left ventricular hypertrophy in human hypertension with irbesartan. J Hypertens 2001, 19:1167-1176.
• [15]Syvanen AC: Detection of point mutations in human genes by the solid-phase minisequencing method. Clin Chim Acta 1994, 226:225-236.
• [16]Suomalainen A, Syvanen AC: Analysis of nucleotide sequence variations by solid-phase minisequencing. Methods Mol Biol 1996, 65:73-79.
• [17]Syvanen AC: Solid-phase minisequencing as a tool to detect DNA polymorphism. Methods Mol Biol 1998, 98:291-298.