Cellular characterization of human epicardial adipose tissue: highly expressed PAPP-A regulates insulin-like growth factor I signaling in human cardiomyocytes

Conover, Cheryl A.; Bale, Laurie K.; Frye, Robert L.; Schaff, Hartzell V.

doi:10.14814/phy2.14006

Cited by 12 publications

(6 citation statements)

References 47 publications

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“…Insulin is well known to play a critical role in triggering and maintaining preadipocyte differentiation. Insulin binds to its receptor and then triggers the phosphorylation of IRS, which, in turn, recruits and sequentially activates PI-3K and AKT [14,15], which plays important roles in adipose biology [37,38]. Although insulin is known to stimulate adipocyte differentiation dose-dependently at the early stage of differentiation [39], Konneker et al recently reported that high concentration of insulin (>3.4 μM) inhibits lipid storage in the late phase of human primary preadipocytes differentiation [40].…”

Section: Discussionmentioning

confidence: 99%

Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro

et al. 2020

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Insulin plays an important role during adipogenic differentiation of animal preadipocytes and the maintenance of mature phenotypes. However, its role and mechanism in dedifferentiation of adipocyte remains unclear. This study investigated the effects of insulin on dedifferentiation of mice adipocytes, and the potential mechanisms. The preadipocytes were isolated from the subcutaneous white adipose tissue of wild type (WT), TNFα gene mutant (TNFα-/-), leptin gene spontaneous point mutant (db/db) and TNFα-/-/db/db mice and were then induced for differentiation. Interestingly, dedifferentiation of these adipocytes occurred once removing exogenous insulin from the adipogenic medium. As characteristics of dedifferentiation of the adipocytes, downregulation of adipogenic markers, upregulation of stemness markers and loss of intracellular lipids were observed from the four genotypes. Notably, dedifferentiation was occurring earlier if the insulin signal was blocked. These dedifferentiated cells regained the potentials of the stem cell-like characteristics. There is no significant difference in the characteristics of the dedifferentiation between the adipocytes. Overall, the study provided evidence that insulin plays a negative regulatory role in the dedifferentiation of adipocytes. We also confirmed that both dedifferentiation of mouse adipocytes, and effect of the insulin on this process were independent of the cell genotypes, while it is a widespread phenomenon in the adipocytes.

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Section: Discussionmentioning

confidence: 99%

Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro

et al. 2020

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“…Epicardial adipose tissue is a visceral fat deposit accumulated between the pericardium and the myocardium, sharing many pathophysiological characteristics with other visceral fat depots (21). It may also cause local inflammation and likely has direct effects on coronary atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…It may also cause local inflammation and likely has direct effects on coronary atherosclerosis. A recent study by Conover et al has shown that PAPP-A is produced in large amount by preadipocytes from human epicardial fat and regulates IGF-I signaling in cardiomyocytes (21). Thus, the authors hypothesize that bioactive products from epicardial fat are disseminated and interact locally with the coronary arteries and heart through the microcirculation, herby accelerating atherosclerotic processes.…”

Section: Discussionmentioning

confidence: 99%

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Local IGF Bioactivity Associates with High PAPP-A Activity in the Pericardial Cavity of Cardiovascular Disease Patients

Hjortebjerg

Rasmussen

Gude

et al. 2020

The Journal of Clinical Endocrinology &Amp; Metabolism

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Objective Pregnancy-associated plasma protein-A (PAPP-A) has been suggested as a proatherogenic enzyme by its ability to locally increase insulin-like growth factor (IGF) activity through proteolytic cleavage of IGF binding protein-4 (IGFBP-4). Recently, stanniocalcin-2 (STC2) was discovered as an inhibitor of PAPP-A. This study aimed to investigate IGFBP-4, PAPP-A, and STC2 as local regulators of IGF bioactivity in the cardiac microenvironment by comparing levels in the pericardial fluid to those in the circulation of patients with cardiovascular disease. Methods Plasma and pericardial fluid were obtained from 39 patients undergoing elective cardiothoracic surgery, hereof 15 patients with type 2 diabetes. Concentrations of IGF-I, intact and fragmented IGFBP-4, PAPP-A, and STC2 were determined by immunoassays and IGF bioactivity by a cell-based assay. Results In pericardial fluid, the concentrations of total IGF-I, intact IGFBP-4, and STC2 were 72±10%, 91±5%, and 40±24% lower than in plasma, while PAPP-A was 15-times more concentrated. The levels of the two IGFBP-4 fragments generated by PAPP-A and reflecting PAPP-A activity were elevated by more than 25%. IGF bioactivity was 62±81% higher in the pericardial fluid than plasma. Moreover, pericardial fluid levels of both IGFBP-4 fragments correlated with the concentration of PAPP-A and with the bioactivity of IGF. All protein levels were similar in pericardial fluid from non-diabetic and diabetic subjects. Conclusions PAPP-A increases IGF bioactivity by cleavage of IGFBP-4 in the pericardial cavity of cardiovascular disease patients. This study provides evidence for a distinct local activity of the IGF system, which may promote cardiac dysfunction and coronary atherosclerosis.

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“…Cells were washed twice with cold PBS and lysed with 150 ul RIPA buffer containing protease and phosphatase inhibitors, as previously described (Conover et al, 2019). Briefly, cells were scraped into microfuge tubes, sonicated, centrifuged and the supernatant transferred to a new tube.…”

Section: Methodsmentioning

confidence: 99%

Pregnancy‐associated plasma protein‐A (PAPP‐A) is a key component of an interactive cellular mechanism promoting pulmonary fibrosis

Bale¹,

Schafer

Atkinson³

et al. 2022

Journal Cellular Physiology

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few effective treatment options. We found a highly significant correlation between pregnancy‐associated plasma protein (PAPP)‐A expression in IPF lung tissue and disease severity as measured by various pulmonary and physical function tests. PAPP‐A is a metalloproteinase that enhances local insulin‐like growth factor (IGF) activity. We used primary cultures of normal adult human lung fibroblasts (NHLF) to test the hypothesis that PAPP‐A plays an important role in the development of pulmonary fibrosis. Treatment of NHLF with pro‐fibrotic transforming growth factor (TGF)‐β stimulated marked increases in IGF‐I mRNA expression (>20‐fold) and measurable IGF‐I levels in 72‐h conditioned medium (CM). TGF‐β treatment also increased PAPP‐A levels in CM fourfold (p = 0.004) and proteolytic activity ~2‐fold. There was an indirect effect of TGF‐β to stimulate signaling through the PI3K/Akt pathway, which was significantly inhibited by both IGF‐I‐inactivating and PAPP‐A inhibitory antibodies. Induction of senescence in NHLF increased PAPP‐A levels in CM 10‐fold (p = 0.006) with attendant increased proteolytic activity. Thus, PAPP‐A is a novel component of the senescent lung fibroblast secretome. In addition, NHLF secreted extracellular vehicles (EVs) with surface‐bound active PAPP‐A that were increased fivefold with senescence. Regulation of PAPP‐A and IGF signaling by TGF‐β and cell senescence suggests an interactive cellular mechanism underlying the resistance to apoptosis and the progression of fibrosis in IPF. Furthermore, PAPP‐A‐associated EVs may be a means of pro‐fibrotic, pro‐senescent communication with other cells in the lung and, thus, a potential therapeutic target for IPF.

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Cellular characterization of human epicardial adipose tissue: highly expressed PAPP-A regulates insulin-like growth factor I signaling in human cardiomyocytes

Cited by 12 publications

References 47 publications

Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro

Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro

Local IGF Bioactivity Associates with High PAPP-A Activity in the Pericardial Cavity of Cardiovascular Disease Patients

Pregnancy‐associated plasma protein‐A (PAPP‐A) is a key component of an interactive cellular mechanism promoting pulmonary fibrosis

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