Mice Lacking Endothelial Angiotensin-Converting Enzyme Have a Normal Blood Pressure

Cole, Justin M.; Quach, Du Le; Sundaram, K.; Corvol, Pierre; Capecchi, Mario R.; Bernstein, Kenneth E.

doi:10.1161/hh0102.102360

Cited by 70 publications

(93 citation statements)

References 20 publications

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“…Note that brain ACE occurs as a doublet, arising from alternate glycosylation. The asterisk indicates a nonspecific band detected only in liver, as has been previously reported (46). B, schematic representation of the human full-length ACE protein.…”

Section: Expression and Characterization Of Transfected Human Ace-tomentioning

confidence: 61%

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

Hemming

Selkoe

2005

Journal of Biological Chemistry

288

211

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Human genetic data have associated angiotensin-converting enzyme (ACE) with Alzheimer disease (AD), and purified ACE has been reported to cleave synthetic amyloid ␤-protein (A␤) in vitro. Whether deficiency in ACE activity, arising from genetic alteration or pharmacological inhibition, can decrease A␤ degradation and allow A␤ accumulation in intact cells is unknown. We cloned ACE from human neuroblastoma cells and showed that it had posttranslational processing and enzymatic activity typical of the endogenous protease. Cellular expression of ACE promoted degradation of naturally secreted A␤40 and A␤42, leading to significant clearance of both species. Using site-directed mutagenesis, we determined that both active sites within ACE contribute to A␤ clearance, and an ACE construct bearing mutations in each catalytic domain had no effect on A␤ levels. Pharmacological inhibition of ACE with a widely prescribed drug, captopril, promoted the accumulation of cell-derived A␤ in the media of ␤-amyloid precursor-protein expressing cells. Together, these results show that ACE can lower the levels of secreted A␤ in living cells and that this effect is blocked by inhibiting the protease's activity with an ACE inhibitor. This work, combined with the genetic studies, supports the hypothesis that ACE may modulate the susceptibility to and progression of AD via degradation of A␤. Our data encourage further analyses of the ACE gene for disease association and raise the question of whether currently prescribed ACE inhibitors could elevate cerebral A␤ levels in humans. An early and pathogenically important feature of Alzheimer disease (AD)2 is the progressive accumulation and deposition of the amyloid ␤-protein (A␤) in brain regions serving memory and cognition. Biochemical, cell biological, animal modeling, genetic, and emerging clinical data all suggest that A␤ is an upstream initiator of the disease process and its associated neuropathology (1-4). Although no proven diseasemodifying treatments are currently available, recent efforts to treat AD have focused on both decreasing the production of A␤ and enhancing its clearance from the brain. One little studied approach to A␤ clearance is augmenting the degradation of the peptide by various proteases expressed in the brain. Thus far, the metalloproteases neprilysin (NEP) (5), insulin-degrading enzyme (IDE) (6), and the endothelin-converting enzymes 1 and 2 (7) have each been implicated as A␤-degrading proteases in the mammalian brain. The serine protease plasmin has been implicated in A␤ degradation in vitro (8), although genetic plasmin deficiency did not promote accumulation of murine A␤ in vivo (9). Supporting a role for therapeutic regulation of A␤-degrading proteases, the overexpression of IDE or NEP in a murine model of AD decreased cerebral A␤ levels and produced significant attenuation of A␤-associated neuropathology (10).Somatic angiotensin-converting enzyme (ACE) is a zinc metalloprotease containing two homologous regions, termed the N-and C-domains, each of which is prot...

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Section: Expression and Characterization Of Transfected Human Ace-tomentioning

confidence: 61%

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

Hemming

Selkoe

2005

Journal of Biological Chemistry

288

211

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“…13,14 The ACE 10/10 mouse is an inbred line (C57Bl/6J) that expresses ACE only in myelomonocytic cells. 13 The ACE 3/3 mouse has a mixed background (C57Bl/6-129) and expresses ACE mostly in hepatocytes.…”

Section: Resultsmentioning

confidence: 99%

“…13 The ACE 3/3 mouse has a mixed background (C57Bl/6-129) and expresses ACE mostly in hepatocytes. 14 Both mouse strains have normal circulating levels of ACE; they also have normal BP and normal baseline renal morphology and function. Importantly, in ACE 10/10 mice, renal ACE activity is totally absent, while in the ACE 3/3 mice it is only 14% of wild-type values.…”

Section: Resultsmentioning

confidence: 99%

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Giani

Janjulia

Kamat

et al. 2014

Journal of the American Society of Nephrology

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The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na + /H + exchanger 3, Na + /Pi co-transporter 2, phosphorylated Na + /K + /Cl 2 cotransporter, and phosphorylated Na + /Cl 2 cotransporter; and greater reductions in abundance and processing of the g isoform of the epithelial Na + channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.

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“…A neomycin cassette (called KT3NP4) was inserted into a unique BssH II restriction site located within the 5Ј untranslated region of somatic ACE. 18 A 4.4-kb ␣-myosin heavy chain (␣-MHC) promoter was cloned by PCR amplification from an ␣-MHC plasmid construct sent to us by Dr. Jim Gulick, Cincinnati Children's Hospital Medical Center. The ␣-MHC promoter was placed immediately 3Ј to the neomycin cassette.…”

Section: Creation Of Ace8 Homozygous Mutant Micementioning

confidence: 99%

“…18 Proper homologous targeting was verified by both genomic Southern blot analysis and by PCR. Chimeric mice were bred to produce agouti F1 offspring; male and female heterozygous F1 mice were used to produce F2 mice.…”

Section: Creation Of Ace8 Homozygous Mutant (Ace 8/8) Micementioning

confidence: 99%

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

Xiao

Fuchs

Campbell

et al. 2004

The American Journal of Pathology

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231

191

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To investigate the local effects of angiotensin II on the heart, we created a mouse model with 100-fold normal cardiac angiotensin-converting enzyme (ACE), but no ACE expression in kidney or vascular endothelium. This was achieved by placing the endogenous ACE gene under the control of the ␣-myosin heavy chain promoter using targeted homologous recombination. These mice, called ACE 8/8, have cardiac angiotensin II levels that are 4.3-fold those of wild-type mice. Despite near normal blood pressure and a normal renal function, ACE 8/8 mice have a high incidence of sudden death. Both histological analysis and in vivo catheterization of the heart showed normal ventricular size and function. In contrast, both the left and right atria were three times normal size. ECG analysis showed atrial fibrillation and cardiac block. In conclusion, increased local production of angiotensin II in the heart is not sufficient to induce ventricular hypertrophy or fibrosis. Instead, it leads to atrial morphological changes, cardiac arrhythmia, and sudden death. The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. A critical component of this system is angiotensin-converting enzyme (ACE), which produces the eight amino acid peptide angiotensin II, the effector molecule of the RAS. 1 ACE is a zinc metallopeptidase located on the cell surface of endothelium. In this location, ACE produces angiotensin II adjacent to vascular smooth muscle, a critical target organ for this vasoconstrictor. ACE is also produced by a variety of other tissues including renal tubular epithelium, activated macrophages, proximal gut epithelium, and areas of the brain. Endothelium and these other tissues make the isozyme of ACE, termed somatic ACE, which consists of two catalytic domains that are independently capable of producing angiotensin II. Studies of knockout mice established that somatic ACE influences blood pressure and other cardiovascular functions. 2,3 In contrast, within the testis, developing male germ cells produce a different ACE isozyme called testis ACE, which plays an important role in normal male reproduction. 4 In addition to regulating normal physiology, substantial evidence suggests that the RAS plays an important role in disease, including heart disease. 5 Genetic studies reported a link between somatic ACE polymorphisms and the incidence of cardiac hypertrophy, sudden cardiac death, and acute coronary events. 6 This is consistent with the clinical effectiveness of ACE inhibitors in treating heart failure. 7 The beneficial effects of ACE inhibitors may not be solely the result of blood pressure reduction since other antihypertensive drugs do not produce the same effect. Rather, ACE may directly influence heart function through the local production of angiotensin II. Studies have found that angiotensinogen, renin, and ACE exist in the heart, implying that local generation of angiotensin II

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Mice Lacking Endothelial Angiotensin-Converting Enzyme Have a Normal Blood Pressure

Cited by 70 publications

References 20 publications

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Mice with Cardiac-Restricted Angiotensin-Converting Enzyme (ACE) Have Atrial Enlargement, Cardiac Arrhythmia, and Sudden Death

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