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PAPP-A and the IGF system in atherosclerosis: what's up, what's down?

ABSTRACT: Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase with a well-established role in releasing bioactive insulin-like growth factor-1 (IGF-1) from IGF-binding protein-2, -4, and -5 by proteolytic processing of these. The IGF system has repeatedly been suggested to be involved in the pathology of atherosclerosis, and both PAPP-A and IGF-1 are proposed biomarkers and therapeutic targets for this disease. Several experimental approaches based on atherosclerosis mouse models have been undertaken to obtain causative and mechanistic insight to the role of these molecules in atherogenesis. However, reports seem conflicting. The literature suggests that PAPP-A is detrimental, while IGF-1 is beneficial. This raises important questions that need to be addressed. Here we summarize the various studies and discuss potential underlying explanations for this seemingly inconsistency with the objective of better understanding complexities and limitations when manipulating the IGF system in mouse models of atherosclerosis. A debate clarifying what's up and what's down is highly warranted going forward with the ultimate goal of improving atherosclerosis therapy by targeting the IGF system.

SUBMITTER: Steffensen LB

PROVIDER: S-EPMC6879922 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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PAPP-A and the IGF system in atherosclerosis: what's up, what's down?

Steffensen Lasse B LB Conover Cheryl A CA Oxvig Claus C

American journal of physiology. Heart and circulatory physiology 20190913 5

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase with a well-established role in releasing bioactive insulin-like growth factor-1 (IGF-1) from IGF-binding protein-2, -4, and -5 by proteolytic processing of these. The IGF system has repeatedly been suggested to be involved in the pathology of atherosclerosis, and both PAPP-A and IGF-1 are proposed biomarkers and therapeutic targets for this disease. Several experimental approaches based on atherosclerosis mouse models have be ...[more]

PMID: 31518159

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Project description:BackgroundPatients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab.MethodsThirty-eight patients with active IBD treated with either prednisolone (n = 17) or infliximab (n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects.ResultsFollowing seven days of prednisolone treatment, total and bioactive IGF-I were increased (p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab (p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments.ConclusionIGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected.Trial registrationClinicalTrials.gov: NCT00955123 . Date of registration: August 7, 2009 (retrospectively registered).

Project description:IntroductionChina has made considerable progress with health system reforms in recent years. Rural China, however, has lagged behind as the diversity of needs of China's 3,000 rural counties were not always well addressed by national top-down reforms. China's Rural Health Reform Project Health XI (HXI) piloted a hybrid process of top down and bottom up implementation of health system reforms which were tailored to rural county level needs and covered a population of more than 21 million. Different studies provide evidence that HXI counties have achieved substantial benefits given the relatively limited investment. The Effectiveness of HXI subsequently raises the question how the hybrid approach may have resulted in effective implementation of interventions. We answer this question to advance understanding of hybrid approaches in general and in the rural Chinese context in particular, where the bottom-up elements might match poorly with the traditional organisational culture and learning style.Materials & methodsWe conducted an in-depth qualitative analysis in three 'best practice' counties, performing document-analyses, observations, semi-structured individual and group interviews. In alignment with the research question, this study is of an explorative nature and follows a sequence of deductive and inductive steps.ResultsHXI struggled initially as counties had difficulties to take initiative and autonomously select and adapt their own reforms. The initial reforms required multiple improvement iterations before achieving the planned results. The effectiveness of these bottom up reform processes has been aided by tight top down supervision and extensive domestic expert involvement. County level leadership is seen as essential to align the top down and bottom up structures and processes. Where successful, HXI has changed mind-sets and counties developed generic health improvement capabilities.ConclusionTailoring innovations to fit local needs formed a severe challenge for the three 'best practice' counties studied. A 'change of mindset' to actively take initiative and assume autonomy was needed to advance. Top down supervision and extensive support of experts was required to overcome the barriers. The studied counties finally achieved sustainable improvements and developed double loop learning capabilities beyond HXI objectives. Taken together, the above findings suggest that the continuum of healthcare reform implementation approaches in which hybrid approaches reside-from bottom up to top down-has two dimensions: a content dimension and a procedural dimension. Enabled by top down procedures, counties were able to bottom up tailor the content of best practice innovations to fit local needs.

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PAPP-A and the IGF system in atherosclerosis: what's up, what's down?

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PAPP-A and the IGF system in atherosclerosis: what's up, what's down?

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