Fatty Acids and Glucose Increase Neutral Endopeptidase Activity in Human Microvascular Endothelial Cells

Muangman, Pornprom; Spenny, Michelle L.; Tamura, Ryuichi; Gibran, Nicole S.

doi:10.1097/01.shk.0000055815.40894.16

Cited by 48 publications

(45 citation statements)

References 35 publications

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“…Because NEP has previously been demonstrated to be regulated by glucose and fatty acids 34 and NEP is produced by adipocytes, 35 it is conceivable that circulating NEP might be correlated with other features of the metabolic syndrome. This is the first study to determine the heritability of circulating NEP, which was estimated to be 22.7%.…”

Section: Discussionmentioning

confidence: 99%

Circulating Activities of Angiotensin-Converting Enzyme, Its Homolog, Angiotensin-Converting Enzyme 2, and Neprilysin in a Family Study

et al. 2006

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Abstract-The renin-angiotensin system is a key regulator of blood pressure (BP), with inhibitors of angiotensinconverting enzyme (ACE) used clinically to treat hypertension and other cardiovascular conditions. ACE2 is a newly identified member of this system, which converts angiotensin II to angiotensin (1-7), and of which the occurrence in plasma has not been investigated. The aim of this study was to determine the heritability of circulating ACE, ACE2, and neprilysin (NEP), which may also be a regulator of BP, in a family study, and to determine covariates that contribute to the variation in plasma activity. ACE, ACE2, and NEP activities were measured in plasma from 534 subjects in the Leeds Family Study using selective fluorogenic substrates. Genetic factors accounted for 24.5%, 67%, and 22.7% of the phenotypic variation in circulating ACE, ACE2, and NEP, respectively. ACE insertion/deletion polymorphism and other measured covariates accounted for 23.8% of variance in circulating ACE. High-density lipoprotein cholesterol was a significant determinant of circulating ACE2. Measured covariates accounted for 17.3% of variation in circulating NEP. ACE and NEP were associated with systolic and diastolic BP in univariate analyses; however, only ACE was independently associated with systolic and diastolic BP after accounting for covariates and shared childhood household. Key Words: angiotensin Ⅲ blood pressure Ⅲ genetics Ⅲ metalloproteinases Ⅲ population T he renin-angiotensin system (RAS) is a complex cascade of bioactive peptides and regulatory enzymes, which acts as a key regulator of blood pressure (BP) and fluid and electrolyte homeostasis. 1 Angiotensin-converting enzyme (ACE) cleaves angiotensin I (Ang I) to form the biologically active peptide angiotensin II (Ang II). Ang II mediates a diverse range of biological effects including vasoconstriction, vascular smooth muscle cell proliferation, and hypertrophy of the heart vessel wall through its interaction with the Ang II type 1 receptor. 2 Although ACE exists primarily as a transmembrane protein on the surface of endothelial and epithelial cells, a soluble form is present in plasma resulting from proteolytic shedding that can be readily measured. 1 The Alu insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene is a strong predictor of plasma ACE levels. 3,4 A recently identified homolog of ACE, ACE2, cleaves Ang II to form Ang (1-7), 5,6 which, in turn, binds to a non-Ang II type 1/Ang II type 2 receptor originally identified as the Mas oncogene 7 and mediates functions that oppose the actions of Ang II. 8 Thus, ACE2 may have a role to counterbalance the action of ACE in producing the vasoconstrictor Ang II, leading to the suggestion that ACE2 and ACE may be correlated. 9 ACE2 displays 42% amino acid identity to ACE and, like ACE, is a type I integral membrane protein that can be proteolytically shed from the plasma membrane. 10 As yet, ACE2 in plasma has not been measured, and its relationship to circulating ACE has not been reported.Neprilysin ([...

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Section: Discussionmentioning

confidence: 99%

Circulating Activities of Angiotensin-Converting Enzyme, Its Homolog, Angiotensin-Converting Enzyme 2, and Neprilysin in a Family Study

et al. 2006

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“…Neprilysin (encoded by Nep , also known as Mme ) is a widely expressed plasma membrane peptidase with increased levels in metabolically altered states [1–3]. We and others have demonstrated that reducing neprilysin activity may be beneficial via improving insulin secretion [4] and sensitivity [5–7].…”

Section: Introductionmentioning

confidence: 99%

Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels

2016

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Aim/hypothesis Neprilysin, a widely expressed peptidase, is upregulated in metabolically altered states such as obesity and type 2 diabetes. Like dipeptidyl peptidase-4 (DPP-4), neprilysin can degrade and inactivate the insulinotropic peptide glucagon-like peptide-1 (GLP-1). Thus, we investigated whether neprilysin deficiency enhances active GLP-1 levels and improves glycaemia in a mouse model of high fat feeding. Methods Nep+/+ and Nep−/− mice were fed a 60% fat diet for 16 weeks, after which active GLP-1 and DPP-4 activity levels were measured, as were glucose, insulin and C-peptide levels during an OGTT. Insulin sensitivity was assessed using an insulin tolerance test. Results High-fat fed Nep−/− mice exhibited elevated active GLP-1 levels (5.8±1.1 vs 3.5±0.8 pmol/l, p<0.05) in association with improved glucose tolerance, insulin sensitivity and beta cell function compared with high-fat fed Nep+/+ mice. In addition, plasma DPP-4 activity was lower in high-fat fed Nep−/− mice (7.4±1.0 vs 10.7±1.3 nmol ml−1 min−1, p<0.05). No difference in insulin:C-peptide ratio was observed between Nep−/− and Nep+/+ mice, suggesting that improved glycaemia does not result from changes in insulin clearance. Conclusions/interpretation Under conditions of increased dietary fat, an improved glycaemic status in neprilysin-deficient mice is associated with elevated active GLP-1 levels, reduced plasma DPP-4 activity and improved beta cell function. Thus, neprilysin inhibition may be a novel treatment strategy for type 2 diabetes.

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“…Neutral endopeptidase is found in many tissues, including vascular tissue, and its activity is increased by fatty acids and glucose in human microvascular cells (13)(14)(15)(16)(17). Interestingly, neutral endopeptidase activity has been shown to be activated by protein kinase C, which is increased in vascular tissues by diabetes (18,19).…”

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confidence: 99%

Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor

et al. 2007

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In epineurial arterioles, acetylcholine-mediated vascular relaxation is mediated by nitric oxide and endotheliumderived hyperpolarizing factor (EDHF), and both mechanisms are impaired by diabetes. The mediator responsible for the effect of EDHF is unknown. In epineurial arterioles, C-type natriuretic peptide (CNP) has properties consistent with EDHF-like activity. Epineurial arterioles express CNP, and exogenous CNP causes a concentration-dependent vascular relaxation. In streptozotocin-induced diabetic rats, CNP-mediated vascular relaxation in epineurial arterioles is decreased. Since CNP may be a regulator of vascular function, a vasopeptidase inhibitor may be an effective treatment for diabetes-induced vascular and neural disease. Vasopeptidase inhibitors inhibit ACE activity and neutral endopeptidase, which degrades natriuretic peptides. Streptozotocin-induced diabetic rats were treated with AVE7688 (450 mg/kg in the diet), a vasopeptidase inhibitor, for 8 -10 weeks after 4 weeks of untreated diabetes. Treatment of diabetic rats corrected the diabetesinduced decrease in endoneurial blood flow, significantly improved motor and sensory nerve conduction velocity, prevented the development of hypoalgesia in the hind paw, and reduced superoxide and nitrotyrosine levels in epineurial arterioles. The diabetes-induced decrease in acetylcholine-mediated vascular relaxation by epineurial arterioles was significantly improved with treatment. These studies suggest that vasopeptidase inhibitors may be an effective approach for the treatment of diabetic vascular and neural dysfunction. Diabetes 56:355-362, 2007 S tudies performed in our laboratory with streptozotocin-induced diabetic rats have provided evidence that the generation of oxidative stress through the production of superoxide and peroxynitrite impairs vascular function of epineurial arterioles of the sciatic nerve, and this precedes slowing of motor nerve conduction velocity (MNCV) (1-3). These studies imply that hyperglycemia-induced oxidative stress may be responsible for diabetes-induced vascular and neural dysfunction that occurs during diabetic neuropathy.We have recently reported that the ACE inhibitor Enalapril was an effective treatment for vascular and neural disease in streptozotocin-induced diabetic rats (4). These results and our studies with C-type natriuretic peptide (CNP), demonstrating its vascular relaxation properties in epineurial arterioles, provide rationale to test the effect of vasopeptidase inhibitors on diabetic neuropathy.It has been reported in mesenteric resistance arteries that release of CNP accounts for the biological activity of endothelium-derived hyperpolarizing factor (EDHF) (5,6). CNP was found to be released from endothelial cells of the perfused rat mesenteric bed in response to endotheliumdependent vasodilators such as acetylcholine (5,6). CNP induced hyperpolarization and relaxation of mesenteric artery vascular smooth muscle through activation of natriuretic peptide receptor subtype B and the same potassium channels that...

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Fatty Acids and Glucose Increase Neutral Endopeptidase Activity in Human Microvascular Endothelial Cells

Cited by 48 publications

References 35 publications

Circulating Activities of Angiotensin-Converting Enzyme, Its Homolog, Angiotensin-Converting Enzyme 2, and Neprilysin in a Family Study

Circulating Activities of Angiotensin-Converting Enzyme, Its Homolog, Angiotensin-Converting Enzyme 2, and Neprilysin in a Family Study

Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels

Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor

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