Human α-defensin regulates smooth muscle cell contraction: a role for low-density lipoprotein receptor–related protein/α2-macroglobulin receptor

Nassar, Taher; Akkawi, Sa’ed; Bar-Shavit, Rachel; Haj‐Yehia, Abdullah; Bdeir, Khalil; Al‐Mehdi, Abu‐Bakr; Tarshis, Mark; Higazi, Abd Al‐Roof

doi:10.1182/blood-2002-04-1080

Cited by 83 publications

(92 citation statements)

References 42 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4c). Potential LF inhibitors would be expected to enter cells to exert their activity against LF, and HNP-1-3 can, indeed, be internalized into host cells (24). Given the described effects of HNP-1 on LeTx, we investigated whether HNP-1 can inhibit LF inside cells.…”

Section: Hnp-1 Is An Inhibitor Of Lfmentioning

confidence: 99%

Human α-defensins neutralize anthrax lethal toxin and protect against its fatal consequences

Kim

Gajendran

Mittrücker

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

140

125

View full text Add to dashboard Cite

Anthrax caused by Bacillus anthracis represents a major bioterroristic threat. B. anthracis produces lethal toxin (LeTx), a combination of lethal factor (LF) and protective antigen that plays a major role in anthrax pathogenesis. We demonstrate that human neutrophil ␣-defensins are potent inhibitors of LF. The inhibition of LF by human neutrophil protein (HNP-1) was noncompetitive. HNP-1 inhibited cleavage of a mitogen-activated protein kinase kinase and restored impaired mitogen-activated protein kinase signaling in LeTx-treated macrophages. HNP-1 rescued murine macrophages from B. anthracis-induced cytotoxicity, and in vivo treatment with HNP-1-3 protected mice against the fatal consequences of LeTx.defensin ͉ innate immunity ͉ Bacillus anthracis

show abstract

Section: Hnp-1 Is An Inhibitor Of Lfmentioning

confidence: 99%

Human α-defensins neutralize anthrax lethal toxin and protect against its fatal consequences

Kim

Gajendran

Mittrücker

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

140

125

View full text Add to dashboard Cite

show abstract

“…HNP1-3 participates in lipoprotein metabolism in the vessel wall, favoring low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] accumulation or modification in the endothelium and extracellular matrix 6,7) . It also impairs endothelium-dependent vasorelaxation 8) , inhibits phenylephrine (PE)-induced artery contraction and PE-mediated Ca 2＋ mobilization in vascular smooth muscle cells (VSMCs) 9) , exhibits prothrombotic activity [10][11][12] , and plays an inhibitory role in various phases of angiogenesis 13) . LL-37 upregulates transcription of monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) in cultured human umbilical vein endothelial cells (HUVECs) and induces the death of VSMCs via apoptosis 4,5) .…”

Section: Biochemical Assaysmentioning

confidence: 99%

Acute ST-Segment Elevation Myocardial Infarction is Associated with Decreased Human Antimicrobial Peptide LL-37 and Increased Human Neutrophil Peptide-1 to 3 in Plasma

Zhao

Yan

Yamashita

et al. 2012

JAT

View full text Add to dashboard Cite

Aim: Increasing evidence indicates that antimicrobial peptides, human neutrophil peptide-1, -2, and -3 (HNP1-3) and human antimicrobial peptide LL-37 are involved in the pathophysiology of atherosclerosis; however, little is known about their circulating protein levels in acute myocardial infarction (AMI). We therefore investigated whether their plasma levels are associated with stable coronary artery disease (CAD) and acute ST-segment elevation myocardial infarction (STEMI). Methods: Systemic or local (culprit artery) blood samples were obtained from 112 consecutive male subjects including no CAD (n = 31) controls, stable CAD (n = 44) and STEMI (n = 47). Plasma HNP1-3 and LL-37 levels were measured by the ready-to-use solid-phase enzyme-linked immunosorbent assay (ELISA) based on the sandwich principle. Results: Systemic HNP1-3 in STEMI was increased compared with no CAD (p=0.000) and stable CAD (p = 0.008), and systemic HNP1-3 in stable CAD was higher than in no CAD (p= 0.004). Systemic LL-37 in STEMI was decreased compared with no CAD (p= 0.009) and stable CAD (p=0.001) and restored within 1 day following STEMI (p = 0.000). Local LL-37 levels in STEMI were higher than systemic levels (p = 0.013). The areas under the ROC curve of systemic HNP1-3 and LL-37 for STEMI were 0.717 (95% CI: 0.624, 0.811; p=0.000) and 0.702 (95% CI: 0.609, 0.795; p = 0.000), respectively. In addition, ischemia time in the STEMI group correlated with systemic and local levels of HNP1-3 (rs = −0.360, p = 0.013; rs = 0.608, p = 0.000, respectively), and was also associated with systemic and local levels of hs-CRP (rs= 0.408, p= 0.004; rs= 0.425, p= 0.003, respectively), but not with those of LL-37 (all p＞0.05). Conclusion: STEMI was associated with transiently decreased LL-37, but persistently increased HNP1-3 in the systemic circulation and the diagnostic accuracy for STEMI were moderate. Future studies should pay more attention to their prognostic values for myocardial infarction.

show abstract

“…The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 1 vate leukocytes and platelets through low density lipoprotein receptor-related protein (LRP) (18,19). However, the cause and effect relationships among these observations in vivo and their relevance to human disease remain to be established.…”

mentioning

confidence: 99%

α-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol

Abu‐Fanne¹,

Maraga²,

Abd‐Elrahman

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Approximately one-half of the patients who develop clinical atherosclerosis have normal or only modest elevations in plasma lipids, indicating that additional mechanisms contribute to pathogenesis. In view of increasing evidence that inflammation contributes to atherogenesis, we studied the effect of human neutrophil ␣-defensins on low density lipoprotein (LDL) trafficking, metabolism, vascular deposition, and atherogenesis using transgenic mice expressing human ␣-defensins in their polymorphonuclear leukocytes (Def ؉/؉ ). Accelerated Def Atherosclerosis and its thrombotic sequel, "atherothrombosis," are likely to remain the predominant cause of death in "developed" countries for decades to come. The etiology of this syndrome is multifactorial, and current predictors provide an incomplete estimate of the risk and opportunity for intervention. In a pooled analysis of over 87,000 persons with diagnosed coronary heart disease, one in five lacked any of the conventional risk factors: hypertension, smoking, high cholesterol, or diabetes (1). Furthermore, half of all cardiovascular events occur in patients with normal lipid levels (2). These data reveal the need to identify and mitigate as yet undescribed, but clinically relevant, risk factors for cardiovascular disease beyond those targeted in current practice.This problem is compounded by the lack of animal models that closely simulate human disease. Animal models used to study atherosclerosis, including its hyperlipidemic (3, 4) and inflammatory (5) components, are often characterized by striking elevations in plasma cholesterol, reaching plasma concentrations of 1500 -2200 mg/dl in LDLR Ϫ/Ϫ and 400 -450 mg/dl in ApoE Ϫ/Ϫ mice fed a high fat diet (3, 4), and most of the cholesterol is found in the VLDL fraction (3, 4). Neither these levels of lipids nor this distribution of lipoproteins is representative of findings in the vast majority of patients with atherosclerosis. Thus, there continues to be a need for new models to identify novel risk factors and novel approaches to intervention.We have identified human ␣-defensins 1-4, also known as human neutrophil peptides (HNPs), 2 as potentially having a role in the development of atherosclerosis. ␣-Defensins are antimicrobial proteins that constitute ϳ5% of the total protein in polymorphonuclear leukocytes (PMNs). ␣-Defensins are released from a subset of azurophilic granules when the PMNs are activated by a variety of agonists (6, 7). ␣-Defensins are abundant in human atherosclerotic coronary and carotid arteries (8, 9), and there is a significant correlation between the deposition of ␣-defensins in skin tissue and the severity of coronary artery disease (10). ␣-Defensins inhibit the degradation of low density lipoprotein (LDL) and Lp(a) by vascular cells (11), increase their binding and retention in extracellular matrix (12), and inhibit tissue-type plasminogen activator (tPA)-mediated fibrinolysis (13, 14).These observations have been confirmed and extended by others. Increased plasma levels of ␣-defensins are assoc...

show abstract

Human α-defensin regulates smooth muscle cell contraction: a role for low-density lipoprotein receptor–related protein/α2-macroglobulin receptor

Abstract: We have previously identified ␣-defensin in association with medial smooth muscle cells (SMCs) in human coronary arteries. In the present paper we report that ␣-defensin, at concentrations below those found in pathological conditions, inhibits phenylephrine (

Cited by 83 publications

References 42 publications

Human α-defensins neutralize anthrax lethal toxin and protect against its fatal consequences

Human α-defensins neutralize anthrax lethal toxin and protect against its fatal consequences

Acute ST-Segment Elevation Myocardial Infarction is Associated with Decreased Human Antimicrobial Peptide LL-37 and Increased Human Neutrophil Peptide-1 to 3 in Plasma

α-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol

Contact Info

Product

Resources

About