Point Mutation in the Stalk of Angiotensin-Converting Enzyme Causes a Dramatic Increase in Serum Angiotensin-Converting Enzyme But No Cardiovascular Disease

Kramers, Cornelis; Danilov, Sergei M.; Deinum, Jaap; Balyasnikova, Irina V.; Scharenborg, Nicole M.; Looman, Maaike W. G.; Boomsma, Frans; Keijzer, M.H. de; Duijn, Cornelia M. van; Martín, Sabrina; Soubrier, Florent; Adema, Gosse J.

doi:10.1161/hc3601.095932

Cited by 46 publications

(72 citation statements)

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“…Indeed, a variety of animal studies and clinical trials have shown that the inhibition of somatic ACE may prevent the decrease in the bioavailability of nitric oxide associated with "endothelial dysfunction" and/or restore endothelial function (Dzau et al, 2002). The physiological/ pathophysiological relevance of soluble ACE is unclear (Xiao et al, 2004) and although a point mutation in the juxtamembrane stalk of ACE causes a dramatic increase in serum ACE levels but no clinical abnormalities (Kramers et al, 2001), elevated plasma ACE levels have been reported to represent a risk factor for cardiovascular diseases (Cambien et al, 1994;Oosterga et al, 1997).…”

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confidence: 99%

Signaling via the Angiotensin-Converting Enzyme Results in the Phosphorylation of the Nonmuscle Myosin Heavy Chain IIA

Kohlstedt

Kellner²,

Busse³

et al. 2005

Mol Pharmacol

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The phosphorylation of the short C-terminal cytoplasmic domain of the somatic angiotensin-converting enzyme (ACE) is involved in the regulation of enzyme shedding. We determined whether the phosphorylation of the cytoplasmic domain of ACE (ACEct) on Ser1270 regulates the cleavage/secretion of the enzyme by affecting its association with other proteins. ACE was associated with ␤-actin and the nonmuscle myosin heavy chain IIA (MYH9) in endothelial cells, as determined by coimmunoprecipitation experiments as well as an ACEct affinity column. The ACE-associated MYH9 immunoprecipitated from 32 P-labeled endothelial cells was basally phosphorylated and cell stimulation with ACE inhibitors, or with bradykinin, increased the phosphorylation of MYH9. Casein kinase 2 (CK2) but not protein kinase C phosphorylated MYH9 in vitro, CK2 coprecipitated with MYH9 from endothelial cells and the phosphorylation of MYH9 in intact cells paralleled the phosphorylation of ACE on Ser1270 by CK2. The CK2 inhibitor 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole attenuated the phosphorylation of ACE and MYH9, disrupted their association, and enhanced the cleavage/secretion of ACE from the plasma membrane. Cytochalasin D decreased the interaction between ACE and MYH9 and stimulated ACE shedding. Although MYH9 was still able to associate with residual amounts of a nonphosphorylatable S1270A ACE mutant, no ACE inhibitor-induced increase in MYH9 phosphorylation could be detected in S1270A-expressing cells. These data indicate that the interaction of ACE with MYH9 determines ACE shedding and is modulated by phosphorylation processes. Furthermore, because ACE inhibitors affect the phosphorylation of MYH9, the phosphorylation of this class II myosin might contribute to the phenomenon of ACE signaling in endothelial cells.

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confidence: 99%

Signaling via the Angiotensin-Converting Enzyme Results in the Phosphorylation of the Nonmuscle Myosin Heavy Chain IIA

Kohlstedt

Kellner²,

Busse³

et al. 2005

Mol Pharmacol

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“…7 Several DNA-mutations in the ACE gene that cause hyperactivity of ACE have been reported. 8,9,12,13 In the Netherlands, the Pro1199Leu missense mutation seems not uncommon. The prevalence is not known; however, on average we identify one patient with familial ACE hyperactivity per 600 ACE measurements.…”

Section: Discussionmentioning

confidence: 99%

“…ACE enters the circulation by its highly regulated proteolytic cleavage from the cell surface of mainly pulmonary and renal endothelial cells. 8,9 Sarcoid granulomas may produce ACE, which explains the elevated serum ACE activity in about 60-70% of patients with active sarcoidosis. 3 Studies have found that the serum ACE activity level correlates with the granuloma burden.…”

Section: Sarcoidosismentioning

confidence: 99%

“…6,9 More recently, polymorphisms in the ACE gene have been identified that cause extremely elevated ACE activity levels of at least 3-fold the upper limit of the reference interval, without apparent clinical symptoms. 9,12,13 One of these mutations is the Pro1199Leu (rs121912703) missense mutation. This mutation causes a conformational change in the juxtamembrane stalk region of the ACE protein, making it more accessible to ACE secretase.…”

Section: Genotypes Influencing Ace Concentrationsmentioning

confidence: 99%

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Extreme elevation of serum angiotensin-converting enzyme (ACE) activity: always consider familial ACE hyperactivity

et al. 2013

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Measurement of serum angiotensin-converting enzyme (ACE) activity can be helpful in the diagnosis and disease monitoring of sarcoidosis. Elevated serum ACE activity is found in 60-70% of sarcoidosis patients. Usually, the ACE activity is mildly increased (<3-fold the upper limit of the reference range) in sarcoidosis patients. Extremely elevated ACE activity is suggestive of the benign condition known as 'familial hyperactivity of ACE'. Familial hyperactivity of ACE is a relatively rare condition and can be confirmed by genetic testing. Considering a genetic cause of strongly elevated serum ACE activity is important to prevent possible overdiagnostics. Here, we highlight the factors that may complicate the interpretation of serum ACE activity measurements, and we present two cases that illustrate the importance of interdisciplinary consultation when extremely elevated serum ACE activity is measured.

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“…Greater immune activity at the inflammation sites (i.e., granulomatous lesions) and higher U Ca (as a result of higher cellular immune system activation at the inflammation sites) can be associated with greater antibody titer, as observed in our study. The negative association of ACE level with antibody response could be questioned because serum ACE level is under the influence of several factors 26 , 27 , 28 …”

Section: Discussionmentioning

confidence: 99%

Influenza vaccination in patients with pulmonary sarcoidosis: efficacy and safety

Tavana

Argani

Gholamin

et al. 2011

Influenza Resp Viruses

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Please cite this paper as: Tavana et al. (2011) Influenza vaccination in patients with pulmonary sarcoidosis: efficacy and safety. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2011.00290.x. Background Sarcoidosis is an inflammatory, granulomatous disorder of unknown etiology. The role of cellular and humoral immune systems in this disease is unclear, whereas dysregulation of the immune system is suggested. Patients with sarcoidosis show diverse responses while exposed to various antigens. Although influenza vaccination is recommended in pulmonary sarcoidosis, its efficacy and safety has not been investigated. Objectives To evaluate safety and immunogenicity of influenza vaccine in patients with sarcoidosis. Patients/Methods Influenza vaccination was performed in 23 eligible patients with sarcoidosis (SP) and 26 healthy controls (HC). Antibody titers against H1N1, H3N2, and B influenza virus antigens were evaluated just before and 1 month after vaccination. Patients were followed for 6 months to assess vaccine safety. Results Serological response and magnitude of changes in antibody titers against influenza vaccine antigens were comparable between SPs and HCs. Women showed a better serological response against B antigen (P = 0·034) than men. Twenty‐four‐hour urine calcium was associated with antibody response against H1N1 [correlation coefficient (CC) = 0·477, P = 0·003] and H3N2 (CC = 0·352, P = 0·028) antigens. Serum angiotensin‐converting enzyme correlated negatively with antibody response against B antigen (CC = −0·331, P = 0·040). Higher residual volume was associated with fewer rises in antibody titer against H3N2 antigen (CC = −0·377, P = 0·035). No major adverse events or disease flare‐up was observed during follow‐up. Conclusions In this study, influenza vaccination did not cause any major adverse event in SPs, and their serological response was equal to HCs. Studies with larger sample size and a broader selection of subjects could help validate the results of this study.

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Point Mutation in the Stalk of Angiotensin-Converting Enzyme Causes a Dramatic Increase in Serum Angiotensin-Converting Enzyme But No Cardiovascular Disease

Cited by 46 publications

References 38 publications

Signaling via the Angiotensin-Converting Enzyme Results in the Phosphorylation of the Nonmuscle Myosin Heavy Chain IIA

Signaling via the Angiotensin-Converting Enzyme Results in the Phosphorylation of the Nonmuscle Myosin Heavy Chain IIA

Extreme elevation of serum angiotensin-converting enzyme (ACE) activity: always consider familial ACE hyperactivity

Influenza vaccination in patients with pulmonary sarcoidosis: efficacy and safety

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