Local enrichment of fatty acid-binding protein 4 in the pericardial cavity of cardiovascular disease patients

Fatty acid binding protein 4 (FABP4), a subtype of fatty acid-binding protein family, shows critical roles in metabolism and inflammation. However, its roles on regulating renal interstitial fibrosis (RIF) remain unclear. In this work, LPS-stimulated in vitro models on NRK-52E and NRK-49F cells, and in vivo UUO models in rats and mice were established. The results showed that comparing with control groups or sham groups, the expression levels of α-SMA, COL1A, COL3A, IL-1β, IL-6, and TNF-α in LPS-stimulated cells or UUO animals were significantly increased. Meanwhile, the levels of TC, TG, and free fatty acid were also significantly increased as well as the obvious lipid droplets, and the serum levels of BUN, Cr were significantly increased with large amounts of collagen deposition in renal tissues. Further investigation showed that compared with control groups or sham groups, the expression levels of FABP4 in LPS-stimulated cells and UUO animals were significantly increased, resulting in down- regulating the expression levels of PPARγ, upregulating the levels of p65 and ICAM-1, and decreasing the expression levels of ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1. To deeply explore the mechanism of FABP4 in RIF, FABP4 siRNA and inhibitor interfered cell models, and UUO model on FABP4 knockout (KO) mice were used. The results showed that the expression levels of α-SMA, COL1A, and COL3A were significantly decreased, the deposition of lipid droplets decreased, and the contents of TC, TG, and free fatty acids were significantly decreased after gene silencing. Meanwhile, the expression levels of PPAR-γ, ACADM, ACADL, SCP-2, CPT1, EHHADH, and ACOX1 were upregulated, the levels of p65 and ICAM-1 were downregulated, and the mRNA levels of IL-1β, IL-6, and TNF-α were decreased. Our results supported that FABP4 contributed to RIF via promoting inflammation and lipid metabolism, which should be considered as one new drug target to treat RIF.

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“…The serum protein levels of FABP4 in rats and mice were measured using the assay kits according to the manufacturer’s instructions 21 .…”

Section: Methodsmentioning

confidence: 99%

RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

et al. 2019

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“…FABP4 mRNA expression in epicardial adipose tissue is profoundly increased compared with its expression in paraaortic adipose tissue in patients with metabolic syndrome 102) . FABP4, mainly derived from epicardial fat, is locally enrich in the pericardial cavity of cardiovascular disease patients 103) . The coronary veno-arterial difference in FABP4 levels in the aortic root and coronary sinus was shown to be an independent predictor of the severity of coronary stenosis after adjustment of conventional risk factors 35) .…”

Section: Circulating Fabp4 Levelmentioning

confidence: 99%

Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases

Furuhashi

2019

J Atheroscler Thromb

209

177

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review Fatty acid-binding proteins (FABPs), a family of lipid chaperones, contribute to systemic metabolic regulation via several lipid signaling pathways. Fatty acid-binding protein 4 (FABP4), known as adipocyte FABP (A-FABP) or aP2, is mainly expressed in adipocytes and macrophages and plays important roles in the development of insulin resistance and atherosclerosis in relation to metabolically driven low-grade and chronic inflammation, referred to as 'metaflammation'. FABP4 is secreted from adipocytes in a non-classical pathway associated with lipolysis and acts as an adipokine for the development of insulin resistance and atherosclerosis. Circulating FABP4 levels are associated with several aspects of metabolic syndrome and cardiovascular disease. Ectopic expression and function of FABP4 in cells and tissues are also related to the pathogenesis of several diseases. Pharmacological modification of FABP4 function by specific inhibitors, neutralizing antibodies or antagonists of unidentified receptors would be novel therapeutic strategies for several diseases, including obesity, diabetes mellitus, atherosclerosis and cardiovascular disease. Significant roles of FABP4 as a lipid chaperone in physiological and pathophysiological conditions and the possibility of FABP4 being a therapeutic target for metabolic and cardiovascular diseases are discussed in this review. Fatty Acid-Binding Proteins (FABPs) Fatty acid trafficking in cells affects many aspects of cellular function 3). Fatty acids act both as an energy source and as signals for metabolic regulations including gene expression, inflammatory and metabolic responses, and growth and survival pathways. Fatty acid-binding proteins (FABPs), a family of intracellular lipid chaperones, regulate lipid trafficking and responses in cells and are linked to metabolic and inflammatory pathways 3-6). FABPs are abundantly expressed 14-15-kDa proteins that reversibly bind hydrophobic ligands, such as long-chain fatty acids and other lipids. It has been proposed that FABPs actively facilitate the transport of fatty acids to specific organelles in the cell for lipid oxidation in the mitochondrion or peroxisome, transcriptional regulation in the nucleus, signaling, trafficking and membrane synthesis in the endoplasmic reticulum (ER), and regula-Copyright©2019 Japan Atherosclerosis Society This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

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“…Pericardial fluid has been shown to be a biologically active compartment of the heart that communicates with the myocardial interstitium and constitutes a unique cardiac microenvironment (2,3). This fluid contains many bioactive compounds that are considered to be products of serum ultrafiltration and leakage from the myocardium toward the pericardial cavity (2,4). Even though the total protein concentration in pericardial fluid is lower than that of serum (3,5), proteins that are produced by the epicardium, myocardium or epicardial adipose tissue may be present at higher concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…Even though the total protein concentration in pericardial fluid is lower than that of serum (3,5), proteins that are produced by the epicardium, myocardium or epicardial adipose tissue may be present at higher concentrations. In cardiovascular disease (CVD), the composition of the myocardial transudate may be altered, and it has been speculated that the pericardial cavity in these patients constitutes a proinflammatory and proatherogenic microenvironment primarily determined by components secreted from the heart, being distinct from the plasma (4,6). However, our knowledge on the protein flow and potential pathophysiological consequence of the pericardial fluid is limited, and understanding the molecular mechanisms could be helpful to elucidate clinical approaches for therapeutic uses (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…We hypothesized that the pericardial cavity of CVD patients, which comprises a proinflammatory coronary atherogenic microenvironment (4,6), contains IGF-I, IGFBP-4, PAPP-A and STC2, partly produced and secreted from the heart and mesothelium, and that the composition differs from that in the circulation. Consequently, pericardial fluid may contain increased IGF bioactivity.…”

Section: Introductionmentioning

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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Local enrichment of fatty acid-binding protein 4 in the pericardial cavity of cardiovascular disease patients

Cited by 8 publications

References 51 publications

RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

RETRACTED ARTICLE: FABP4 contributes to renal interstitial fibrosis via mediating inflammation and lipid metabolism

Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases

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

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