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Byline: Joyita. Banerjee, Abhishek. Gupta, Vertica. Agnihotri, Rashmita. Pradhan, Ramesh. Kandel, Ashish. Upadhyay, Sadanand. Dwivedi, Lalit. Kumar, Sharmistha. Dey, Aparajit. Dey Background: rs4340ID polymorphism of angiotensin-converting enzyme (ACE) correlates with [...]

The study of experimental hypertension and the development of drugs with selective inhibitory effects on the enzymes and receptors constituting the components of the circulating and tissue renin-angiotensin systems have led to newer concepts of how this system participates in both physiology and pathology. Over the last decade, a renewed emphasis on understanding the role of angiotensin-(1-7) and angiotensin-converting enzyme 2 in the regulation of blood pressure and renal function has shed new light on the complexity of the mechanisms by which these components of the renin angiotensin system act in the heart and in the kidneys to exert a negative regulatory influence on angiotensin converting enzyme and angiotensin II. The vasodepressor axis composed of angiotensin-(1-7)/angiotensin-converting enzyme 2/mas receptor emerges as a site for therapeutic interventions within the renin-angiotensin system. This review summarizes the evolving knowledge of the counterregulatory arm of the renin-angiotensin system in the control of nephron function and renal disease. blood pressure; hypertension; renal function; renin; renal disease doi: 10.1152/ajprenal.00110.2010.

Angiotensin-converting enzyme 2 (ACE2) is expressed at high levels in the kidney and converts angiotensin II (ANG II) to ANG-(1-7). We studied the effects of ACE2 inhibition and ANG-(1-7) in the 5/6 nephrectomy (5/6 Nx) mouse model of chronic kidney disease (CKD). Male FVB mice underwent sham surgery (Sham) or 5/6 Nx and were administered either vehicle, the ACE2 inhibitor MLN-4760 (MLN), the [AT.sub.1] receptor antagonist losartan, MLN plus losartan, or ANG(1-7) for 4 wk. In 5/6 Nx mice with or without MLN, kidney cortical ACE2 protein expression was significantly decreased at 4 wk, compared with Sham. Inhibition of ACE2 caused a decrease in renal cortical ACE2 activity. Kidney cortical ACE expression and activity did not differ between groups of mice. In 5/6 Nx mice treated with MLN, kidney levels of ANG II were significantly increased, compared with Sham. 5/6 Nx induced a mild but insignificant increase in blood pressure (BP), a 50% reduction in FITC-inulin clearance, and a significant increase in urinary albumin excretion. ACE2 inhibition in 5/6 Nx mice did not affect BP or FITC-inulin clearance but significantly increased albuminuria compared with 5/6 Nx alone, an effect reversed by losartan. Treatment of 5/6 Nx mice with ANG-(1-7) increased kidney and plasma levels of ANG-(1-7) but did not alter BP, FITC-inulin clearance, or urinary albumin excretion, and it increased relative mesangial area. These data indicate that kidney ACE2 is downregulated in the early period after 5/6 Nx. Inhibition of ACE2 in 5/6 Nx mice increases albuminuria via an [AT.sub.1] receptor-dependent mechanism, independent of BP. In contrast, ANG-(1-7) does not affect albuminuria after 5/6 Nx. We propose that endogenous ACE2 is renoprotective in CKD. renin-angiotensin system; nephrectomy; albuminuria doi: 10.1152/ajprenal.00426.2009.

This study was performed to investigate the impact of acute hyperglycemia (HG) on the permeability of the normal glomerular filtration barrier in vivo. In anesthetized Wistar rats (250-280 g), the left ureter was catheterized for urine collection, while simultaneously blood access was achieved. Rats received an intravenous (iv) infusion of either 1) hypertonic glucose to maintain blood glucose at 20-25 mM (G; n = 8); 2) hypertonic glucose as in 1) and a RhoA-kinase inhibitor (Y-27632; Rho-G; n = 8); 3) 20% mannitol (MANN; n = 7) or 4) hypertonic (12%) NaCl to maintain plasma crystalloid osmotic pressure ([[pi].sub.cry]) at ~320-325 mosmol/1 (NaCl; n = 8) or 5) physiological saline (SHAM; n = 8). FITC-Ficoll 70/400 was infused iv for at least 20 min before termination of the experiments, and plasma and urine were collected to determine the glomerular sieving coefficients ([theta]) for polydisperse Ficoll (molecular radius 15-80 [Angstrom]) by high-performance size-exclusion chromatography. In G there was a marked increase in [theta] for [Fico11.sub.55-80[Angstrom]] at 20 min, which was completely reversible within 60 min and abrogated by a Rho-kinase (ROCK) inhibitor, while glomerular permeability remained unchanged in MANN and NaC1. In conclusion, acute HG caused rapid, reversible increases in [theta] for large Ficolls, not related to the concomitant hyperosmolarity, but sensitive to ROCK inhibition. The changes observed were consistent with the formation of an increased number of large pores in the glomerular filter. The sensitivity of the permeability changes to ROCK inhibition strongly indicates that the cytoskeleton of the cells in the glomerular barrier may be involved in these alterations. microalbuminuria; RhoA-kinase; podocytes; endothelium; hyperosmolarity doi: 10.1152/ajprenal.00710.2009.

In rat diabetic animal models, ANG(1-7) treatment prevents the development of cardiovascular complications. Angiotensin-converting enzyme (ACE)2 is a major ANG(1-7)-generating enzyme in vascular smooth muscle cells (VSMCs), and its expression is decreased by a prolonged exposure to high glucose (HG), which is reflected by lower ANG(1-7) levels. However, the underlying mechanism of its downregulation is unknown and was the subject of this study. Rat aortic VSMCs were maintained in normal glucose (NG) or HG (~4.1 and ~23.1 mmol/l, respectively) for up to 72 h. Several PKC and NADPH oxidase inhibitors and short interfering (si)RNAs were used to determine the mechanism of HG-induced ACE2 downregulation. Cell lysates were subjected to Western blot analysis, real-time quantitative PCR, and ANG(1-7) radioimmunodetection. At 72 h of HG exposure, ACE2 mRNA, protein, and ANG(1-7) levels were decreased (0.17 [+ or -] 0.01-, 0.47 [+ or -] 0.03-, and 0.16 [+ or -] 0.01-fold, respectively), and the expression of NADPH oxidase subunit Noxl was increased (1.70 [+ or -] 0.2-fold). The HG-induced ACE2 decrease was reversed by antioxidants and Nox1 siRNA as well as by inhibitors of glycotoxin formation. ACE2 expression was PKC-[beta]II dependent, and PKC-[beta]II protein levels were reduced in the presence of HG (0.32 [+ or -] 0.03-fold); however, the PKC-[beta]II inhibitor CG-53353 prevented the HG-induced ACE2 loss and Nox1 induction, suggesting a nonspecific effect of the inhibitor. Our data suggest that glycotoxin-induced Noxl expression is regulated by conventional PKCs. ACE2 expression is PKC-[beta]II dependent. Nox1-derived superoxides reduce PKC-[beta]II expression, which lowers ACE2 mRNA and protein levels and consequently decreases ANG(1-7) formation. angiotensin-coverting enzyme 2/angiotensin-(1-7); NADPH oxidase; smooth muscle; vascular smooth muscle cells; glycotoxins; protein kinase C-[beta]II

In the current study, we investigated the expression and activity of ACE2 during pregnancy in normotensive and hypertensive rats, focusing on the relative contribution of the uterus and the placentas, the kidney serving as a reference. We used the Sabra rat model of salt-sensitive hypertension. We confirmed a systemic vasodilatory state during the third trimester of pregnancy, as evidenced by a reduction in blood pressure, both in normotensive and hypertensive rats. At the time that blood pressure was reduced, ACE2 was expressed abundantly in the reproductive organs. The relative levels of ACE2 mRNA in the pregnant animal were placenta > kidneys [greater than or equal to] uterus and of ACE2 activity kidney > placenta > uterus. In the uterus and the placenta, ACE2 expression was unaffected by strain, salt-loading, or the level of blood pressure. ACE2 activity in the uterus of the nonpregnant rat was not affected by any of these variables either, but during pregnancy increased in salt-loaded animals. When estimating the total contribution of the uterus to ACE2 mRNA and activity during pregnancy, we found that the amount of ACE2 mRNA increased in both strains irrespective of diet, but that ACE2 activity increased only in salt-loaded animals. We further estimated the relative total contribution of the uterus, placentas, and kidneys to ACE2 expression and activity during pregnancy by adjusting for mass and number of organs and found that the placentas were the major contributors, followed by the kidney and the uterus. We conclude that during pregnancy, the placentas, in particular, but also the uterus, constitute important sources of ACE2, in addition to its normal production in the kidney, leading to an estimated twofold increase in total ACE2 activity. These data are consistent the hypothesis that transient ACE2 overexpression and increased activity during pregnancy may be important in modulating systemic, as well as local hemodynamics in the uteroplacental unit. uterus; placenta; activity

Byline: Adrian Plunkett (1), Rachel S. Agbeko (1), KaWah Li (2), Steve E. Humphries (2), Nigel J. Klein (3), Mark J. Peters (1) Keywords: Angiotensin-converting enzyme; Acute respiratory distress syndrome; Child; Genetic polymorphism Abstract: Objective The D allele of the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of ARDS in critically ill adults and severity of bronchopulmonary dysplasia in pre-term infants. We hypothesised that the presence of the hypoxia-associated ACE D allele would increase susceptibility to acute hypoxic respiratory failure (AHRF) in a cohort of critically ill children. Design and setting Single-centre prospective observational cohort study. Patients Children under 16 years of age requiring admission to a tertiary general PICU. Measurements and results A total of 216 Caucasian patients were enrolled. Thirty (13.9%) children developed AHRF and 13 were diagnosed with ARDS (6.0%). There was no significant difference in ACE D allele frequency between patient groups with or without AHRF (0.53 vs. 0.54). Conclusions Variation in ACE activity does not influence the development of paediatric AHRF. This may reflect a different pathogenesis from adult ARDS. Author Affiliation: (1) Paediatric Intensive Care Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK (2) Department of Medicine, Centre for Cardiovascular Genetics, University College London, London, UK (3) Infectious Diseases and Microbiology Unit, Institute of Child Health, London, UK Article History: Registration Date: 26/08/2008 Received Date: 20/05/2008 Accepted Date: 20/08/2008 Online Date: 12/09/2008

Angiotensin converting enzyme (ACE) has been shown to be involved in regulation of apoptosis in nonintestinal tissues. This study examined the role of ACE in the modulation of intestinal adaptation utilizing ACE knockout mice ([ACE.sup.-/-]). A 60% small bowel resection (SBR) was used, since this model results in a significant increase in intestinal epithelial cell (EC) apoptosis as well as proliferation. Baseline villus height, crypt depth, and intestinal EC proliferation were higher, and EC apoptosis rates were lower in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice. After SBR, EC apoptosis rates remained significantly lower in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice. Furthermore, villus height and crypt depth after SBR continued to be higher in [ACE.sup.-/-] mice. The finding of a lower bax-to-bcl-2 protein ratio in [ACE.sup.-/-] mice may account for reduced EC apoptotic rates after SBR in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice. The baseline higher rate of EC proliferation in [ACE.sup.-/-] compared with [ACE.sup.+/+] mice may be due to an increase in the expression of several EC growth factor receptors. In conclusion, ACE appears to have an important role in the modulation of intestinal EC apoptosis and proliferation and suggests that the presence of ACE in the intestinal epithelium has a critical role in guiding epithelial cell adaptive response. short bowel syndrome; bax; bcl-2; intestine; adaptation

Byline: Jesus Villar (1,2,3), Carlos Flores (2,4,5), Lina Perez-Mendez (2,6), Nicole Maca-Meyer (4), Elena Espinosa (7), Jesus Blanco (2,8), Ruben Sanguesa (7), Arturo Muriel (8), Paula Tejera (4), Mercedes Muros (2,9), Arthur S. Slutsky (3,10) Keywords: Association study; Genetic susceptibility; Genetic variation; Human sepsis Abstract: Objective The insertion/deletion (I/D) of a 289 base pair Alu repeat sequence polymorphism in the angiotensin-converting enzyme gene (ACE) has been shown to predict susceptibility and outcome in the acute respiratory distress syndrome (ARDS). We hypothesized that the I/D polymorphism also confers susceptibility to sepsis and is a predisposing factor for morbidity and mortality of patients with severe sepsis. Design and setting Case-control study including 212 consecutive patients fulfilling criteria for severe sepsis admitted to a Spanish network of postsurgical and critical care units, and 364 population-based controls. Susceptibility to severe sepsis was evaluated as primary outcome mortality in severe sepsis, susceptibility to sepsis-induced ARDS, and mortality in sepsis-induced ARDS were examined as secondary outcomes. An additive model of inheritance in which patients were classified into three genotype groups (II, ID, and DD) was used for association testing. Measurements and results Genotype and allele frequencies of I/D were distributed similarly in all septic, ARDS, and non-ARDS patients and in population-based controls. ACE I/D polymorphism was not associated with severe sepsis susceptibility or mortality. The ACE I/D polymorphism was associated neither with sepsis-induced ARDS susceptibility (pa-=a-0.895) or mortality (pa-=a-0.950). These results remained nonsignificant when adjusted for other covariates using multiple logistic regression analysis or Kaplan--Meier estimates of 28-day survival. Conclusions Our data do not support an association of the ACE gene I/D polymorphism with susceptibility or mortality in severe sepsis or with sepsis-induced ARDS in Spanish patients. Author Affiliation: (1) Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrin, Barranco de la Ballena, s/n - 4th floor, south wing, 35010, Las Palmas de Gran Canaria, Canary Islands, Spain (2) Instituto de Salud Carlos III, CIBER de Enfermedades Respiratorias, Madrid, Spain (3) Keenan Research Center, St. Michael's Hospital, Toronto, Ontario, Canada (4) Division of Human Genetics, Research Unit, Hospital Universitario NS de Candelaria, Tenerife, Spain (5) Department of Medicine, Division of Pulmonary and Critical Care, University of Chicago, Chicago, Ill, USA (6) Division of Clinical and Genetic Epidemiology, Research Unit, Hospital Universitario NS de Candelaria, Tenerife, Spain (7) Department of Anesthesia, Hospital Universitario NS de Candelaria, Tenerife, Spain (8) Intensive Care Unit, Hospital Universitario Rio Hortega, Valladolid, Spain (9) Department of Clinical Biochemistry, Hospital Universitario NS de Candelaria, Tenerife, Spain (10) Department of Medicine, Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada Article History: Registration Date: 06/11/2007 Received Date: 28/05/2007 Accepted Date: 17/09/2007 Online Date: 05/12/2007 Article note: This research was supported by grants from FUNCIS (53/04) and the Ministerio de Educacion y Ciencia, Spain (SAF2004-06833). J.V. is the principal investigator in both grants. The authors named above wrote this article on behalf of the GRECIA and GEN-SEP groups. The members of the GRECIA and GEN-SEP groups are listed under Acknowledgements at the end of the article. J. Villar, C. Flores, and L. Perez-Mendez contributed equally to this work. Electronic supplementary material The online version of this article (doi: 10.1007/s00134-007-0937-z) contains supplementary material, which is available to authorized users.

Like humans, savannah baboons (Papiosp.) show heritable interindividual variation in complex physiological phenotypes. One prominent example of such variation involves production of the homeostatic regulator protein angiotensin converting enzyme (ACE), which shows heritable variation in both baboons and humans. In humans, this phenotypic variation is associated with an Alu insertion-deletion polymorphism in the ACE gene, which explains approximately half of the variation in serum ACE activity. We identified a similar Alu insertion-deletion polymorphism in the baboon ACE homologue and measured its frequency in a wild population and a captive population of baboons. We also analyzed the contribution of ACE genotype at this indel to variation in serum ACE activity in the captive population. When conditioned on weight, a known factor affect ing ACE activity in humans, age and ACE genotype both accounted for variance in ACE activity; in particular, we identified a significant nonadditive interaction between age and genotype. A model incorporating this interaction effect explained 21.6% of the variation in residual serum ACE activity. Individuals homozygous for the deletion mutation exhibited significantly higher levels of ACE activity than insertion-deletion heterozygotes at younger ages (10-14 years), but showed a trend towards lower levels of ACE activity compared with heterozygotes at older ages ([greater than or equal to]15 years). These results demonstrate an interesting parallel between the genetic architecture underlying ACE variation in humans and baboons, suggesting that further attention should be paid in humans to the relationship between ACE genetic variation and aging. KEY WORDS angiotensin converting enzyme; genotype-phenotype; Amboseli; parallel evolution

Byline: Koichi Nakanishi (1), Mayumi Sako (1), Nahoko Yata (1), Noriyuki Aoyagi (1), Kandai Nozu (2), Ryojiro Tanaka (2), Kazumoto Iijima (3), Norishige Yoshikawa (1,4) Keywords: Promoter; Urinary protein excretion; Heavy proteinuria; Polymerase chain reaction; Restriction fragment length polymorphism Abstract: We have previously reported that the TT genotype of the angiotensinogen gene and the ID/DD genotype of the angiotensin-converting enzyme gene are associated with increased severity of proteinuria in IgA nephropathy in Japanese children. Recently it was reported that polymorphism at -20 from adenine to cytosine in the angiotensinogen gene, increasing the level of this transcript, was associated with the progression of renal dysfunction in adult IgA nephropathy. We therefore investigated whether this polymorphism is involved in IgA nephropathy in Japanese children. We identified this polymorphism in 105 children with IgA nephropathy and 119 healthy adults using polymerase chain reaction/restriction fragment length polymorphism analysis. At the time of biopsy, all patients had normal blood pressure and renal function. There were no differences in the genotypes and allele frequencies of this polymorphism between patients with IgA nephropathy and controls. The number of patients with the AC/CC genotype showing heavy proteinuria (aSS1.0 g/day per m.sup.2 body surface area) at biopsy was significantly higher than that with the AA genotype (P=0.039, chi-squared test). The AC/CC genotype of this polymorphism may be associated with an increased severity of proteinuria, suggesting that this polymorphism may play a significant role in the progression of IgA nephropathy in Japanese children. Author Affiliation: (1) Department of Pediatrics, Wakayama Medical University, Wakayama-City, Wakayama, Japan (2) Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan (3) Department of Nephrology, National Center for Child Health and Development, Setagaya, Tokyo, Japan (4) Department of Pediatrics, Wakayama Medical University, Kimiidera 811--1, Wakayama City, Wakayama 641--8510, Japan Article History: Registration Date: 17/10/2003 Received Date: 28/04/2003 Accepted Date: 29/09/2003 Online Date: 28/11/2003

The effects of citrullination and its involvement in several human diseases, including rheumatoid arthritis and multiple sclerosis is discussed. Peptidylarginine deiminase (PAD, EC 3.5.3.15) enzymes catalyze the conversion of arginine residues to citrulline residues in proteins.

Background. Genetic polymorphisms of angiotensin-converting enzyme (ACE) and apolipoprotein E (APOE) have been reported to be associated with human longevity and dementia in the elderly. However, whether such putative longevity genes exert the same effects on different ethnic groups living in different environments is not well known. Methods. We investigated the distributions of the ACE and APOE genotypes and their relations with dementia status in Korean centenarians by cross-sectional study. A total of 103 centenarians (13 men and 90 women, mean age 102.4 [+ or -] 2.6 years) were included in this study. The allele frequencies of the genes were compared with those of two control groups: 7232 apparently healthy adults (4100 men and 3132 women) of mean age 48.5 [+ or -] 9.6 years for the ACE genotyping, and 6435 adults (5008 men and 1427 women) of mean age 50.7 [+ or -] 7.9 years for the APOE genotyping. The dementia status of the centenarians was assessed by clinical psychologist using the Clinical Dementia Rating (CDR) score. Results. The frequencies of genotypes and alleles of the ACE and APOE genes of the centenarians were not significantly different from those of the control groups. There was a lack of association between presence of the D allele on the ACE gene and dementia status. However, the frequency of the [epsilon]4 allele of the APOE gene was significantly higher in centenarians with dementia than in centenarians without definitive dementia (9.1% versus 1.5%, p < .05). Conclusions. These results suggest that neither the ACE nor the APOE gene is significantly associated with longevity in the Korean population, but that the APOE [epsilon]4 allele is still related with dementia even at age 100 and older.

The Angiotensin-converting enzyme (Ance) gene of Drosophila melanogaster is a homologue of mammalian angiotensin-converting enzyme (ACE), a peptidyl dipeptidase implicated in regulation of blood pressure and male fertility. In Drosophila, Ance protein is present in vesicular structures within spermatocytes and immature spermatids. It is also present within the lumen of the testis and the waste bag, and is associated with the surface of elongated spermatid bundles. Ance mRNA is found mainly in large primary spermatocytes and is not detectable in cyst cells. Testes lacking germ cells have reduced levels of ACE activity, and no Ance protein is detectable by immunocytochemistry, indicating that the germ cells are the major site of Ance synthesis. Ance mutant testes lack individualised sperm and have very few actin-based individualisation complexes. Spermatid nuclei undergo scattering along the cyst and have abnormal morphology, similar to other individualisation mutants. Mutant spermatids also have abnormal ultrastructure with grossly defective mitochondrial derivatives. The failure of Ance mutant testes to form individualisation complexes may be due to a failure in correct spermatid differentiation. Taken together, the expression pattern and mutant phenotype suggest that Ance is required for spermatid differentiation, probably through the processing of a regulatory peptide synthesised within the developing cyst. Keywords: Ance; Metallopeptidase; Spermatogenesis; ACE; Spermatid individualisation

Byline: A. Nobilis (1), I. Kocsis (2), P. Toth-Heyn (3), A. Treszl (2), A. Schuler (4), T. Tulassay (2), B. Vasarhelyi (2) Keywords: Keywords Acute renal failure; Very low birth weight infant; Angiotensin converting enzyme; Angiotensin II type 1 receptor; Genetic polymorphism Abstract: High neonatal activity of the renin-angiotensin system (RAS) is crucial for the maintenance of glomerular filtration of the newborn. The aim of the present study was to investigate whether genetic polymorphisms leading to lower angiotensin converting enzyme activity (ACE) or impaired functionality of angiotensin II (AII) type 1 receptor (AT1R) might predispose very low birth weight newborns (VLBWs) to the development of acute renal failure (ARF). The medical records of 110 VLBW infants were analyzed. ARF developed in 42 of them during the first postnatal week, while 68 neonates exhibited normal renal function. The ACE I/D polymorphism and the [A.sup.1166]C variants of AT1R were determined from dried blood samples. The frequency of the ACE I allele did not differ in ARF and non-ARF groups (0.307 and 0.284) the frequency of the AT1R C.sup.1166 variant was also the same in ARF and non-ARF groups (0.250 and 0.227). Although low activity of RAS has been implicated in the development of neonatal ARF and data indicated that the functionality of RAS is influenced by the I/D variants of the ACE gene and the [A.sup.1166]C variant of the AT1R gene, we could not demonstrate any effect of these polymorphisms on the development of ARF in VLBW infants. Author Affiliation: (1) Second Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary, HU (2) Joint Research Program of the First Department of Pediatrics and the Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary, HU (3) First Department of Pediatrics, Semmelweis University, Bokay u. 53, 1083 Budapest, Hungary. Vasbar@gyer1.sote.hu, HU (4) Budai Children&apos;s Hospital PKU Laboratory, Budapest, Hungary, HU Article note: Received: 7 March 2001 / Revised: 9 August 2001 / Accepted: 10 August 2001

Testis angiotensin-converting enzyme (ACE) is a unique form of ACE, only produced by male germ cells, and results from a testis-specific promoter found within the ACE gene. We have investigated the role of cAMP-response element modulator (CREM)[Tau] in testis ACE transcription. In gel shift experiments, testes nuclear proteins retard an oligonucleotide containing the cAMP-response element (CRE) found at position -55 in the testis ACE promoter. Anti-CREM antibody supershifts this complex. Competitive gel shift shows that recombinant CREM[Tau] protein and testes nuclear proteins have a similar specificity of binding to the testis ACE CRE. Functional analysis using in vitro transcription and transfection studies also demonstrate that CREM[Tau] protein is a transcriptional activator of the testis ACE promoter. Western blot analysis identifies CREM[Tau] protein in the protein-DNA complex formed between nuclear proteins and the testis ACE CRE motif. This analysis also identified other CREM isoforms in the gel-shifted complex, which are thought to be CREM[Tau]1/2, CREM[Alpha]/[Beta], and S-CREM. These data indicate that CREM[Tau] isoforms play an important role as a positive regulator in the tissue-specific expression of testis ACE.

The angiotensin-converting-enzyme (ACE) gene does not appear to significantly influence left ventricular mass or increase the genetic risk of developing an enlarged left heart heart. It has been speculated that carriers of the D allele of the ACE gene have a greater incidence for some heart disorders, especially those involving the left ventricle. DNA samples and echocardiographic data from 2,439 people were compiled and compared to identify any risk of left ventricular problems associated with the ACE gene. No difference in the prevalence of left ventricular mass or heart enlargement was found to be related to any particular genotype of the ACE gene. Further comparisons of the genotypes and polymorphic data found no relationship between the ACE locus and left ventricular mass.

The presence of a specific mutation in the gene for angiotensin-converting enzyme may not be a good marker for an increased risk of coronary artery disease. A total of 1,250 male physicians in the Physicians' Health Study had developed coronary artery disease 10 years after the study began. They were matched with 2,340 male physicians in the same study who did not develop coronary heart disease (the control group). Researchers used the polymerase chain reaction to test blood samples for the presence of a mutation of the gene for angiotensin-converting enzyme. The risk of coronary artery disease was no greater in the men who had the mutation. In fact, 31% of the men in the control group had the mutation. Previous studies have found an increased risk of coronary artery disease in people who have the mutation.

Left ventricular hypertrophy (LVH) (enlargement of the heart) may be related to genetic background. Specifically, it may be related to a deletion-insertion polymorphism of the angiotensin-converting-enzyme (ACE) gene. Other factors that may influence left ventricular hypertrophy are absence of an elevated cardiac workload, obesity, hemodynamic overload, and environmental factors. LVH is a risk factor for cardiovascular disease. Electrocardiography was used to identify and measure LVH in 290 of 1,428 German patients studied. Men who were homozygous for the ACE genotype, or who had two identical alleles (alternative form of a gene) at one locus (position of a gene on a chromosome), had a 2.63 greater occurrence of LVH than other men. Sixty-two percent of subjects with LVH did not have hypertension, weakening any correlation between the two.

The factors inducing neutrophils to change angiotensin-converting enzyme (ACE) activity in cultured pulmonary endothelial cells were studied. It was observed that neutrophils mediate endothelial ACE dysfunction through factors that resemble those influencing cell lysis and augmented permeability. A model for the evaluation of neutrophil-mediated endothelial cell damage in the early stages was developed. It was concluded that polymorphonuclear leukocytes (PMN)-mediated ACE dysfunction may be caused by the synthesis of hydrogen peroxide by PMN, and its subsequent change to hydroxyl radicals.

The DD genotype linked with higher concentrations of circulating angiotensin-converting enzyme (ACE) occurs more often among myocardial infarction patients with low-body mass index and low plasma levels of ApoB than among controls. This indicates that the ACE/ID polymorphism is a powerful risk factor both for myocardial infarction and for coronary heart disease in general. This new risk factor will apply to many people once thought to be in little danger of developing heart problems.

The dcp gene isolated from plasmids pBR328 library of Salmonella chromosomal DNA was cloned, sequenced, and its messenger RNA (mRNA) analyzed to characterize the gene. The gene consists of a 2.8 kilobase region with an open reading frame for a 77,269 kilodalton protein corresponding to dipeptidyl carboxypeptidase as determined by electrophoresis and gel filtration. mRNA analysis revealed that the gene is not cotranscribed with any other gene. The amino acid sequence deduced from the nucleotide sequence bears a striking similarity to a peptidase coded for by the opdA gene.