1636

ACE

ACE1|CD143|DCP|DCP1|ICH|MVCD3;angiotensin I converting enzyme (peptidyl-dipeptidase A) 1;ACE;angiotensin I converting enzyme (peptidyl-dipeptidase A) 1

CD143 antigen|angiotensin I converting enzyme peptidyl-dipeptidase A 1 transcript|angiotensin converting enzyme, somatic isoform|angiotensin-converting enzyme|carboxycathepsin|dipeptidyl carboxypeptidase 1|dipeptidyl carboxypeptidase I|kininase II|peptida

17q23.3

protein-coding

Count: ACE; 1636

Angiotensin converting enzyme (ACE) plays an important role in the pathogenesis of pulmonary hypertension. In this study we determined whether the deletion (D)/insertion (I) polymorphism in the ACE gene may be associated with pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease (COPD). ACE genotypes were determined in 19 patients with COPD. All patients underwent right heart catheterization followed by a constant-load exercise test while breathing room air or oxygen. Subgroups were created of seven patients with the II genotype, six with the ID genotype, and six with the DD genotype who were well-matched with respect to age, blood gas data at rest or after exercise, baseline lung function, results of incremental exercise testing, and hemodynamic data at rest. The mean pulmonary arterial pressure (Ppa) and pulmonary vascular resistance (Rpv) at rest in the three subgrpoups did not differ significantly during breathing of either room air or oxygen. However, the Ppa after exercise challenge in patients with the DD genotype (55.7 +/- 4.9 mm Hg [mean +/- SD]) was significantly higher than in patients with the II genotype (42.6 +/- 7.1 mm Hg, p = 0.008). The Rpv after exercise in patients with the DD genotype was also significantly higher than in patients with the ID and II genotypes. During breathing of oxygen to diminish acute hypoxic pulmonary vasoconstriction, the Ppa in patients with the DD genotype (52.3 +/- 3.1 mm Hg) was higher than in patients with the ID genotype (40.5 +/- 5.9 mm Hg, p = 0.0049) or the II genotype (37.7 +/- 5.9 mm Hg, p = 0.0027). In addition, the Rpv in patients with the DD genotype was higher than in patients with the ID and II genotypes. These results suggest that D-I polymorphism in the ACE gene may be associated with pulmonary hypertension evoked by exercise challenge in patients with COPD. However, the number of patients in this study was very small for a genetic association study, and our results should be examined in larger studies.

STUDY OBJECTIVES: We have recently determined that the angiotensin-converting enzyme (ACE) DD genotype might be associated with pulmonary hypertension during exercise in patients with COPD. Therefore, this study was designed to determine whether ACE gene polymorphisms adversely affect tissue oxygenation during exercise in patients with COPD. DESIGN: Cross-sectional analysis. SETTING: University hospital. PATIENTS: Thirty-nine patients (14 patients with II genotype, 12 patients with ID genotype, and 13 patients with DD genotype). INTERVENTIONS: All patients underwent right-heart catheterization and constant-load exercise testing for 5 min on an ergometer. Measurements and results: The ratio of the change in oxygen delivery (DO(2)) to the increase in oxygen consumption (O(2)) during exercise (DeltaDO(2)/DeltaO(2)) was significantly lower in patients with the DD genotype (1.5 +/- 0.2) than in those with the II genotype (1.9 +/- 0.3, p = 0.0006) and the ID genotype (1.7 +/- 0.2, p = 0.037). Mixed venous oxygen tension (PO(2)) after exercise in patients with the DD genotype (23.5 +/- 1.5 mm Hg) was also significantly lower than in patients with the II genotype (26.7 +/- 1.6 mm Hg, p = 0.0002) and the ID genotype (25.0 plus minus 2.0 mm Hg, p = 0.045). In addition, the change in plasma concentration of lactate during exercise (DeltaLactate) was significantly higher in patients with DD genotype (33.3 +/- 4.3 mmol/L) than in those with the II genotype (25.5 +/- 3.6 mmol/L, p = 0.0002) and the ID genotype (28.8 +/- 4.0 mmol/L, p = 0.029). The mean pulmonary arterial pressure after exercise was significantly correlated with DeltaDO(2)/DeltaO(2) (r = - 0.423, p = 0.0076) but not with PvO(2) after exercise and with DeltaLactate. CONCLUSIONS: The ACE DD genotype may be associated with an impairment in peripheral tissue oxygenation during exercise in patients with COPD.

OBJECTIVE: Pulmonary endothelial dysfunction is intertwined with the development and progression of pulmonary arterial hypertension (PAH). Pulmonary endothelium is an active metabolic tissue in healthy human subjects. This study was undertaken to determine the effects of PAH on pulmonary endothelial angiotensin-converting enzyme (ACE) activity and to identify differences between common PAH types, i.e., PAH related to connective tissue disease (PAH-CTD) versus idiopathic PAH (IPAH). METHODS: Nineteen patients with PAH-CTD, 25 patients with IPAH, and 23 control subjects were evaluated. The single-pass transpulmonary percent metabolism (%M) and hydrolysis (both reflecting enzyme activity per capillary) of an ACE synthetic substrate were determined. In addition, the calculated functional capillary surface area (FCSA), normalized to body surface area (BSA), was determined. RESULTS: The %M values in patients with PAH-CTD (mean+/-SEM 53.6+/-3.6%) were significantly reduced compared with those in control subjects (P<0.01) and those in patients with IPAH (P<0.03), but were similar between the IPAH and control groups (mean+/-SEM 66.2+/-3.6% and 74.7+/-2.7%, respectively). Substrate hydrolysis was also significantly reduced in patients with PAH-CTD. The FCSA/BSA was significantly reduced in patients with PAH-CTD (mean+/-SEM 1,068+/-118 ml/minute/m2) and in patients with IPAH (1,443+/-186 ml/minute/m2) compared with that in controls (2,948+/-245 ml/minute/m2; P<0.01 for both). At a given cardiac index, the FCSA/BSA tended to be lower in the PAH-CTD group than in the IPAH group. Moreover, unlike in IPAH, a linear relationship between the FCSA/BSA and the diffusing capacity for carbon monoxide (DLCO) was observed in PAH-CTD (r=0.54, P<0.03). CONCLUSION: The metabolically functional pulmonary capillary bed appears to be reduced to an equal extent in PAH-CTD and IPAH. However, %M and hydrolysis appear to be reduced in PAH-CTD but not in IPAH, reflecting relatively diminished ACE activity on the pulmonary capillary endothelial cells of patients with PAH-CTD, and showing that pulmonary endothelial metabolic function differs between PAH types. This study also provides the first functional evidence that a reduced DLCO value in patients with PAH-CTD is related to the degree of FCSA loss.

OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) polymorphisms including I/D and 2 single-nucleotide polymorphisms (SNP) affect susceptibility to systemic sclerosis (SSc) in a large French Caucasian population. METHODS: A case-control study was performed in 494 patients with SSc and 280 healthy controls for I/D polymorphism. Two supplementary exonic SNP of ACE gene (rs4309, rs4362) were genotyped in 659 patients with SSc and 511 matched healthy controls. Among the whole SSc population, 453 (67%) patients with SSc had the limited cutaneous subtype, 47 (7%) had precapillary pulmonary arterial hypertension, 209 (32%) had digital ulcers, and 10 (1.5%) had renal crisis. A combined analysis of the available results for ACE I/D genotypes in Caucasians was also performed. RESULTS: There was no association between the 3 polymorphic markers and SSc for allelic and genotype frequencies. No association was observed for the different vascular subsets of the disease. Haplotype analyses did not detect any association. The lack of association for ACE I/D was confirmed by the combined analysis. CONCLUSION: These results in a large cohort of European Caucasian patients with SSc do not support that the ACE gene is implicated in the pathogenesis of SSc and its vascular damage.

BACKGROUND: pulmonary arterial hypertension (PAH) is a rare, lethal disease associated with single gene disorders, connective tissue disease, exposures to anorexigens, and often, idiopathic etiology. Genes can modify the risk of PAH: (1) monogenic disorders associated with PAH are incompletely penetrant, and (2) not all patients with associated conditions at increased risk for PAH develop the disease. The renin angiotensin aldosterone system (RAAS) provides a set of candidate genes that could modulate pulmonary vascular disease similar to its effects on renal and peripheral vasculature. METHODS: We studied 247 patients with PAH, comprising 177 with idiopathic PAH (IPAH), 63 with PAH/connective tissue disease (CTD), and 7 with PAH associated with anorexigens. Patients were genotyped for 5 common polymorphisms in angiotensinogen (AGT), angiotensin-converting enzyme (ACE), cardiac chymase A (CMA1), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2). Genotypes were tested for associations with age at diagnosis, hemodynamic parameters at diagnosis, and/or response to acute pulmonary vasodilator testing at diagnosis. RESULTS: Associations were demonstrated for AGTR1 and age at diagnosis in IPAH (p = 0.005). Homozygotes for the 1166C allele (n = 13) were associated with an age at diagnosis 26 years later than those with A/A (n = 139) or A/C (n = 90) genotypes. No associations were demonstrated for AGT, ACE, CMA1, or CYP11B2. CONCLUSIONS: The 1166C polymorphism in AGTR1 appears to be associated with a later age at diagnosis in IPAH, suggesting that this pathway could be involved in the biologic variability that is known to occur in PAH.