Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

Funalot, Benoît; Ouimet, Tanja; Clapéron, Audrey; Fallet, C.; Delacourte, A.; Epelbaum, Jacques; Subkowski, Thomas; Léonard, Nadine; Codron, Valérie; David, J-P; Amouyel, Philippe; Helbecque, Nicole

doi:10.1038/sj.mp.4001612

Cited by 20 publications

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“…This gender difference may be partially due to the fact that the higher levels of estrogen in women suppress ET-1 synthesis to a greater extent, so women are more sensitive to the increase of ECE-1 activity45. However, this effect was not seen in a related study of human Alzheimer’s disease for which ECE-1 activity also plays an important role28 (see below). In our experimental settings, the elevated BP existed in both female and male E2F2 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor

Zhou

Zhu

Cheng³

et al. 2009

Circulation

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Background-Recent studies have identified a polymorphism in the endothelin-converting enzyme (ECE)-1b promoter (Ϫ338C/A) that is strongly associated with hypertension in women. The polymorphism is located in a consensus binding sequence for the E2F family of transcription factors. E2F proteins are crucially involved in cell-cycle regulation, but their roles in cardiovascular function are poorly understood. Here, we investigated the potential role of E2F2 in blood pressure regulation. Methods and Results-Tail-cuff measurements of systolic and diastolic blood pressures were significantly higher in E2F2-null (E2F2 Ϫ/Ϫ ) mice than in their wild-type littermates, and in ex vivo ring assays, aortas from the E2F2 Ϫ/Ϫ mice exhibited significantly greater contractility in response to big endothelin-1. Big endothelin-1 is activated by ECE-1, and mRNA levels of ECE-1b, the repressive ECE-1 isoform, were significantly lower in E2F2Ϫ/Ϫ mice than in wild-type mice. In endothelial cells, chromatin immunoprecipitation assays confirmed that E2F2 binds the ECE-1b promoter, and promoter-reporter assays indicated that E2F2 activates ECE-1b transcription. Furthermore, loss or downregulation of E2F2 led to a decline in ECE-1b levels, to higher levels of the membranous ECE-1 isoforms (ie,, and to deregulated ECE-1 activity. Finally, Sam68 coimmunoprecipitated with E2F2, occupied the ECE-1b promoter (chromatin immunoprecipitation), and repressed E2F2-mediated ECE-1b promoter activity (promoter-reporter assays). Conclusion-Our results identify a cell-cycle-independent mechanism by which E2F2 regulates endothelial function, arterial contractility, and blood pressure. Key Words: blood pressure Ⅲ endothelin Ⅲ endothelium Ⅲ E2F transcription factors Ⅲ Sam68 protein, mouse E ndothelin-1 (ET-1) is a potent vessel-constricting peptide. 1 It is synthesized in endothelial cells (ECs) from a larger preproET-1 precursor that is cleaved into an inactive 38 -amino-acid peptide, big ET-1 (BigET-1), and then further processed by endothelin-converting enzyme-1 (ECE-1) into the active, 21-amino-acid ET-1. 2 Subsequently, ET-1 acts on the smooth muscle cells through 2 receptors of the G-proteincoupled receptor family, ET A and ET B . 3,4 Ample evidence from genetic mouse models and from the blockade of ET-1 receptors in humans has demonstrated that the ET-1/ECE-1 system plays a critical role in the regulation of blood pressure (BP) homeostasis. 5,6 Clinical Perspective on p 1221 ECE-1 is a membrane-bound zinc metalloendopeptidase expressed predominantly in the vascular endothelium 7 and catalyzes the rate-limiting step during biogenesis of ET-1. 2 The physiological importance of the conversion of BigET-1 to mature ET-1 is demonstrated by observations in ECE-1-, ET-1-, and ET A -knockout animals, which exhibit virtually identical cardiac and craniofacial abnormalities during embryonic development, 5,8 and by the Ϸ140-fold greater vasoconstrictive potency of ET-1. 2 There are 4 isoforms of ECE-1: ECE-1a, -1b, -1c, and -1d, which are expressed via ...

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Section: Discussionmentioning

confidence: 99%

“…Human pECE-1b/ C -AP and pECE-1b/ A -AP plasmids were provided by Dr. Benoit Funalot (INSERM, France)28. pRC/CMV-E2F1 and pRC/CMV-E2F2 plasmids were provided by Dr. Farbio Martelli (IRCSS, Italy).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor

Zhou

Zhu

Cheng³

et al. 2009

Circulation

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“…The enzyme is able to hydrolyse some biological active peptides such as bradykinin, neurotesin, substantion P and oxidized chain of insulin B (Johnson et al, 1999). Ability of endothelin-converting enzyme to degrade amyloid peptide has been discovered in experiments with a metallopreoteinase inhibitorphosphoramid and then its positive effect was verified in human brain (Funalot et al, 2004).…”

Section: Endothelin-converting Enzymementioning

confidence: 99%

Alzheimer's Disease: Definition, Molecular and Genetic Factors

Babušíková¹,

Evinová²,

Jurečeková³

et al. 2011

Advanced Understanding of Neurodegenerative Diseases

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“…Two different ECEs, including ECE-1 and ECE-2, are expressed in brain regions related to AD [45, 46]. Although ECE-1 is abundantly expressed in vascular endothelial cells [47], it is also expressed in nonvascular cells, including hippocampal and neocortical pyramidal neurons, cerebellar Purkinje cells, and astrocytes [48].…”

Section: Endothelin-converting Enzymes (Eces)mentioning

confidence: 99%

“…Another study demonstrated that NEP (−/−)/ECE-1 (+/−) or NEP (−/−)/ECE-2 (−/−) mice have increased accumulation of both A β 1–40 and A β 1–42 in the brain [51]. Interestingly, a genetic variant of human ECE-1 (ECE1B C-338A) with increased promoter activity was associated with a reduced risk of sporadic AD in a French Caucasian population [45]. ECE-1 degrades synthetic A β levels in vitro [50] and is the main ECE for A β degradation.…”

Section: Endothelin-converting Enzymes (Eces)mentioning

confidence: 99%

Protein Kinase C‐Regulated Aβ Production and Clearance

Kim

Hinton

Choi

2011

International Journal of Alzheimer's Disease

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Alzheimer's disease (AD) is the most common form of dementia among the elderly population. AD, which is characterized as a disease of cognitive deficits, is mainly associated with an increase of amyloid β-peptide (Aβ) in the brain. A growing body of recent studies suggests that protein kinase C (PKC) promotes the production of the secretory form of amyloid precursor protein (sAPPα) via the activation of α-secretase activity, which reduces the accumulation of pathogenic Aβ levels in the brain. Moreover, activation of PKCα and mitogen-activated protein kinase (MAPK) is known to increase sAPPα. A novel type of PKC, PKCε, activates the Aβ degrading activity of endothelin converting enzyme type 1 (ECE-1), which might be mediated via the MAPK pathway as well. Furthermore, dysregulation of PKC-MAPK signaling is known to increase Aβ levels in the brain, which results in AD phenotypes. Here, we discuss roles of PKC in Aβ production and clearance and its implication in AD.

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Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease

Cited by 20 publications

References 0 publications

Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor

Regulation of Vascular Contractility and Blood Pressure by the E2F2 Transcription Factor

Alzheimer's Disease: Definition, Molecular and Genetic Factors

Protein Kinase C‐Regulated Aβ Production and Clearance

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