Pregnancy-Associated Plasma Protein A and Its Endogenous Inhibitor, the Proform of Eosinophil Major Basic Protein (proMBP), Are Related to Complex Stenosis Morphology in Patients With Stable Angina Pectoris

Cosı́n-Sales, Juan; Christiansen, Michael; Kaminski, Paul F.; Oxvig, Claus; Overgaard, Michael Toft; Cole, Della; Holt, David W.; Kaski, Juan Carlos

doi:10.1161/01.cir.0000124716.67921.d2

Cited by 85 publications

(47 citation statements)

References 42 publications

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“…PAPP-A and its endogenous inhibitor, the proform of eosinophil major basic protein, are related to complex stenosis morphology in patients with stable angina pectoris. 53 PAPP-A levels Ͼ10 mIU/L were found to identify ACS with a sensitivity of 89% and a specificity of 81%, but the study population was small. 54 A larger population was studied by Lund and colleagues, 55 who found a strong correlation between PAPP-A and the combined end point death-MI-revascularization at 6 months in 200 patients with ACS.…”

Section: Other Inflammatory Markersmentioning

confidence: 77%

CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease

Biasucci¹

2004

Circulation

153

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Abstract-Inflammation is a recognized key component of acute coronary syndromes. Such pathogenetic achievement has led to the use of inflammatory cells and proteins as prognostic markers in these syndromes. A number of markers have been proposed, including proinflammatory cytokines such as interleukin-6, interleukin-1RA, and tumor necrosis factor-␣, adhesion molecules such as intracellular adhesion molecule-1 and vascular adhesion molecule-1 and markers of cell activation. Although all are of scientific interest, the clinical use of these markers is limited by their high cost, low availability, and unfavorable biological profile. Conversely, common markers of inflammation such as C-reactive protein (CRP), the prototypic acute phase protein, and to a lesser extent fibrinogen, have been proven to be reliable and important markers of risk in ischemic heart disease. CRP, in particular, has been found to be associated with short-and long-term prognosis in acute coronary syndromes, including ST-elevation myocardial infarction, and in stable angina, and to predict the risk of restenosis and major events, including death, after revascularization procedures. CRP has been consistently found to be independent from other risk factors and to have an incremental value beyond the common risk factors and biochemical markers of risk, including troponin. Whether CRP also should be used as a guide to therapy is still a matter of discussion that deserves further, properly designed studies. Key Words: AHA Scientific Statements Ⅲ inflammation Ⅲ revascularization Ⅲ angina Ⅲ risk factors S hort-and long-term prediction of risk in patients with acute coronary syndromes (ACS) is a challenging clinical problem. Despite diagnostic and therapeutic advances, the rate of event recurrence is still relatively high (in the range of 14% to 16% at 6 months 1,2 ). The growing evidence that inflammation plays a pivotal role in the pathogenesis of most of the cases of ACS 3 led to the use of inflammatory mediators as markers of risk in these syndromes. 4 As consistent data have been accumulated in this area, risk prediction in ischemic heart disease and in ACS in particular represents the main use of inflammatory markers in cardiovascular medicine. More recently, sparse but intriguing data have been published suggesting that inflammatory markers may represent a marker of risk in other cardiovascular conditions. C-Reactive ProteinA number of inflammatory mediators have been studied as markers of risk in ischemic heart disease. They are discussed separately. Although many of them are of potential clinical interest (discussed below), C-reactive protein (CRP) is the inflammatory marker most extensively assessed in prognostic studies and is an almost perfect marker of inflammation (it has a half-life of 19 hours and is neither consumed nor produced during the reaction). This is the result, in part, of analytical reasons because of the availability of high-sensitivity, relatively low-cost methods for its measurement and in part because of its biological pr...

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Section: Other Inflammatory Markersmentioning

confidence: 77%

CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease

Biasucci¹

2004

Circulation

153

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“…Hypoxic/oxidative/inflammatory stresses are capable of enhancing PAPP-A's bioactivity (13,14). In addition, experimental damage induces an increase in local PAPP-A expression and IGF-I bioactivity (14,15) with immunomodulatory and anti-inflammatory actions (13). These data suggest that PAPP-A is involved in the physiological repair and replicative programs through its product: free IGF-I (13,14).…”

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confidence: 98%

Epithelial lining fluid free IGF-I-to-PAPP-A ratio is associated with bronchopulmonary dysplasia in preterm infants

Capoluongo

Ameglio

Lulli

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Preterm newborns developing retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) show persistently low levels of insulin-like growth factor-I (IGF-I) in sera. They also present higher free IGF-I concentrations in epithelial lining fluids (ELFs) and lung tissues. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that dissociates three binding proteins from the active form of IGF-I, namely free IGF-I. The present study analyzes the ELF concentrations of free IGF-I, PAPP-A, and their ratios in preterm newborns developing or not BPD, defined as O2 dependence at 36 wk postmenstrual age. Bronchoalveolar lavage fluids of 41 infants (34 without and 7 with BPD) were analyzed on the 2nd and 4th day after birth. Infants developing BPD showed increased ELF free IGF-I and decreased PAPP-A concentrations on both days 2 and 4 compared with newborns without BPD. A nonsignificant trend between these 2 days was observed for free IGF-I (increasing) and PAPP-A (decreasing). On the same days, the free IGF-I-to-PAPP-A ratio was always significantly higher in patients developing BPD. These differences were more significant than those of IGF-I or PAPP-A when individually evaluated. A multivariate analysis confirmed the significance for free IGF-I on day 4, whereas the ratio was confirmed on both days 2 and 4. The same ratio was significantly correlated with some indexes of disease severity, such as hours of oxygen administration, days of hospitalization, and ROP severity scores. Finally, the ratio between ELF free IGF-I and PAPP-A appears to be a useful marker for lung injury of premature newborns.

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“…Through this proteolytic activity, PAPP-A causes the release of active IGF and thereby regulates its bioavailability in several biological systems. In particular, the role of PAPP-A has been studied in ovarian follicular development (4), implantation (5), fetal development (6 -8), wound healing (9), and atherosclerosis (10,11).…”

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confidence: 99%

A Substrate Specificity-determining Unit of Three Lin12-Notch Repeat Modules Is Formed in Trans within the Pappalysin-1 Dimer and Requires a Sequence Stretch C-terminal to the Third Module

Weyer

Boldt

Poulsen

et al. 2007

Journal of Biological Chemistry

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Members of the pappalysin family of metzincin metalloproteinases, pregnancy-associated plasma protein-A (PAPP-A, pappalysin-1) and PAPP-A2 (pappalysin-2), regulate the bioavailability of insulin-like growth factors (IGFs) by specific proteolytic inactivation of IGF-binding proteins (IGFBPs). PAPP-A cleaves IGFBP-4 and IGFBP-5, whereas PAPP-A2 cleaves only IGFBP-5. The pappalysins contain three Lin12-Notch repeat (LNR1-3) modules, previously considered unique to the Notch receptor family in which they function to regulate receptor cleavage. In contrast to the Notch receptor where three LNR modules are tandemly arranged, LNR3 is separated by more than 1000 residues from LNR1-2 in the pappalysin sequence. Each of the three LNR modules of PAPP-A is required for proteolysis of IGFBP-4, but not IGFBP-5. However, we here find that a C-terminal truncated variant of PAPP-A, which lacks LNR3 and therefore activity against IGFBP-4, cleaves IGFBP-4 when co-expressed with a PAPP-A variant, which is mutated in the active site. This suggests that LNR3 from the inactive subunit interacts in trans with LNR1-2 of the truncated PAPP-A subunit to form a functional trimeric LNR unit. We also show that formation of such a functional LNR unit depends on dimerization, as dissociation of a mutated non-covalent PAPP-A dimer results in reduced activity against IGFBP-4, but not IGFBP-5. Using PAPP-A/PAPP-A2 chimeras, we demonstrate that PAPP-A2 LNR1-2, but not LNR3, are functionally conserved with respect to IGFBP proteolysis. Additionally, we find that a sequence stretch C-terminal to LNR3 and single residues (Asp 1521 , Arg 1529 , and Asp 1530 ) within this are required for LNR functionality.The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A, pappalysin-1, EC 3.4.24.79) 2 is secreted as a disulfide-linked 400-kDa homodimer (1) that cleaves insulinlike growth factor binding proteins (IGFBP)-4 (2) and IGFBP-5 (3). Through this proteolytic activity, PAPP-A causes the release of active IGF and thereby regulates its bioavailability in several biological systems. In particular, the role of PAPP-A has been studied in ovarian follicular development (4), implantation (5), fetal development (6 -8), wound healing (9), and atherosclerosis (10, 11). PAPP-A is the founding member of the pappalysin family (12, 13) within the metzincin superfamily of metalloproteinases (14, 15), also including its only known homologue, PAPP-A2, which cleaves IGFBP-5, but not IGFBP-4 (16). The 1558 3 -residue PAPP-A2 shares 46% of its residues with the 1547-residue PAPP-A (17), and they display the same domain organization with a laminin G-like domain and a proteolytic domain in the N-terminal part (18), a central region of ϳ500 residues with unknown domain composition, and a C-terminal part with five complement control protein (CCP) modules that mediate cell surface adhesion of 20). The pappalysins also contain three Lin12-Notch repeat (LNR) modules, previously considered unique to the Notch receptor family. But in contrast to the Notch receptors, which...

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Pregnancy-Associated Plasma Protein A and Its Endogenous Inhibitor, the Proform of Eosinophil Major Basic Protein (proMBP), Are Related to Complex Stenosis Morphology in Patients With Stable Angina Pectoris

Cited by 85 publications

References 42 publications

CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease

CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease

Epithelial lining fluid free IGF-I-to-PAPP-A ratio is associated with bronchopulmonary dysplasia in preterm infants

A Substrate Specificity-determining Unit of Three Lin12-Notch Repeat Modules Is Formed in Trans within the Pappalysin-1 Dimer and Requires a Sequence Stretch C-terminal to the Third Module

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