scholarly journals Myeloid GRK2 Regulates Obesity-Induced Endothelial Dysfunction by Modulating Inflammatory Responses in Perivascular Adipose Tissue

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 953
Author(s):  
María González-Amor ◽  
Rocío Vila-Bedmar ◽  
Raquel Rodrigues-Díez ◽  
Rosa Moreno-Carriles ◽  
Alba C. Arcones ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Endothelial Dysfunction ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Aortic Aneurysms ◽  
Perivascular Adipose Tissue ◽  
Abdominal Aortic ◽  
Factor Α ◽  
G Protein Coupled ◽  
Grk2 Expression

Perivascular adipose tissue (PVAT) is increasingly being regarded as an important endocrine organ that directly impacts vessel function, structure, and contractility in obesity-associated diseases. We uncover here a role for myeloid G protein-coupled receptor kinase 2 (GRK2) in the modulation of PVAT-dependent vasodilation responses. GRK2 expression positively correlates with myeloid- (CD68) and lymphoid-specific (CD3, CD4, and CD8) markers and with leptin in PVAT from patients with abdominal aortic aneurysms. Using mice hemizygous for GRK2 in the myeloid lineage (LysM-GRK2+/−), we found that GRK2 deficiency in myeloid cells allows animals to preserve the endothelium-dependent acetylcholine or insulin-induced relaxation, which is otherwise impaired by PVAT, in arteries of animals fed a high fat diet (HFD). Downregulation of GRK2 in myeloid cells attenuates HFD-dependent infiltration of macrophages and T lymphocytes in PVAT, as well as the induction of tumor necrosis factor-α (TNFα) and NADPH oxidase (Nox)1 expression, whereas blocking TNFα or Nox pathways by pharmacological means can rescue the impaired vasodilator responses to insulin in arteries with PVAT from HFD-fed animals. Our results suggest that myeloid GRK2 could be a potential therapeutic target in the development of endothelial dysfunction induced by PVAT in the context of obesity.

scholarly journals Niacin protects against abdominal aortic aneurysm formation via GPR109A independent mechanisms: role of NAD+/nicotinamide

2019 ◽  
Vol 116 (14) ◽  
pp. 2226-2238 ◽  
Author(s):  
Tetsuo Horimatsu ◽  
Andra L Blomkalns ◽  
Mourad Ogbi ◽  
Mary Moses ◽  
David Kim ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Cell ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Aortic Aneurysms ◽  
Cell Infiltration ◽  
Protective Effects ◽  
Abdominal Aortic ◽  
G Protein Coupled

Abstract Aims Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. Methods and results Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. Conclusion Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

scholarly journals Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms

2017 ◽  
Vol 65 (4) ◽  
pp. 1171-1179.e1 ◽  
Author(s):  
Maggie Folkesson ◽  
Emina Vorkapic ◽  
Erich Gulbins ◽  
Lukasz Japtok ◽  
Burkhard Kleuser ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Cells ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Perivascular Adipose Tissue ◽  
Abdominal Aortic

scholarly journals Relationships Between Perivascular Adipose Tissue and Abdominal Aortic Aneurysms

2021 ◽  
Vol 12 ◽  
Author(s):  
Tongtong Ye ◽  
Guangdong Zhang ◽  
Hangyu Liu ◽  
Junfeng Shi ◽  
Hongyan Qiu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Therapeutic Target ◽  
Abdominal Aortic Aneurysms ◽  
Normal Function ◽  
Aneurysm Rupture ◽  
Aortic Aneurysms ◽  
Cell Phenotype ◽  
Unique Type ◽  
Perivascular Adipose Tissue ◽  
Abdominal Aortic

Abdominal aortic aneurysms (AAAs) are typically asymptomatic, and there is a high mortality rate associated with aneurysm rupture. AAA pathogenesis involves extracellular matrix degradation, vascular smooth muscle cell phenotype switching, inflammation, and oxidative stress. There is increasing evidence of excessive adipocyte accumulation in ruptured AAA walls. These excessive numbers of adipocytes in the vascular wall have been closely linked with AAA progression. Perivascular adipose tissue (PVAT), a unique type of adipose tissue, can be involved in adipocyte accumulation in the AAA wall. PVAT produces various chemokines and adipocytokines around vessels to maintain vascular homeostasis through paracrine and autocrine mechanisms in normal physiological conditions. Nevertheless, PVAT loses its normal function and promotes the progression of vascular diseases in pathological conditions. There is evidence of significantly reduced AAA diameter in vessel walls of removed PVAT. There is a need to highlight the critical roles of cytokines, cells, and microRNA derived from PVAT in the regulation of AAA development. PVAT may constitute an important therapeutic target for the prevention and treatment of AAAs. In this review, we discuss the relationship between PVAT and AAA development; we also highlight the potential for PVAT-derived factors to serve as a therapeutic target in the treatment of AAAs.

scholarly journals Inflammatory Activity of Human Perivascular Adipose Tissue in Abdominal Aortic Aneurysms

2020 ◽  
Vol 1 ◽  
pp. 251
Author(s):  
Jorn P. Meekel ◽  
Marina Dias-Neto ◽  
Natalija Bogunovic ◽  
Gloria Conceição ◽  
Claudia Sousa-Mendes ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Inflammatory Activity ◽  
Perivascular Adipose Tissue ◽  
Abdominal Aortic

scholarly journals Role of Adipokines and Perivascular Adipose Tissue in Abdominal Aortic Aneurysm: A Systematic Review and Meta-Analysis of Animal and Human Observational Studies

2021 ◽  
Vol 12 ◽  
Author(s):  
Shivshankar Thanigaimani ◽  
Jonathan Golledge
Keyword(s):  
Systematic Review ◽  
Adipose Tissue ◽  
Animal Models ◽  
Animal Studies ◽  
Meta Analysis ◽  
Aortic Aneurysms ◽  
Perivascular Adipose Tissue ◽  
Abdominal Aortic ◽  
Meta Analyses

Improved understanding of abdominal aortic aneurysms (AAA) pathogenesis is required to identify treatment targets. This systematic review summarized evidence from animal studies and clinical research examining the role of adipokines and perivascular adipose tissue (PVAT) in AAA pathogenesis. Meta-analyses suggested that leptin (Standardized mean difference [SMD]: 0.50 [95% confidence interval (CI): −1.62, 2.61]) and adiponectin (SMD: −3.16 [95% CI: −7.59, 1.28]) upregulation did not significantly affect AAA severity within animal models. There were inconsistent findings and limited studies investigating the effect of resistin-like molecule-beta (RELMβ) and PVAT in animal models of AAA. Clinical studies suggested that circulating leptin (SMD: 0.32 [95% CI: 0.19, 0.45]) and resistin (SMD: 0.63 [95% CI 0.50, 0.76]) concentrations and PVAT to abdominal adipose tissue ratio (SMD: 0.56 [95% CI 0.33, 0.79]) were significantly greater in people diagnosed with AAA compared to controls. Serum adiponectin levels were not associated with AAA diagnosis (SMD: −0.62 [95% CI −1.76, 0.52]). One, eight, and one animal studies and two, two, and four human studies had low, moderate, and high risk-of-bias respectively. These findings suggest that AAA is associated with higher circulating concentrations of leptin and resistin and greater amounts of PVAT than controls but whether this plays a role in aneurysm pathogenesis is unclear.

Abstract 107: Depletion of Plasmacytoid Dendritic Cells Inhibits Experimental Abdominal Aortic Aneurysms

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Baohui Xu ◽  
Haojun Xuan ◽  
Naoki Fujimura ◽  
Sara A Michie ◽  
Ronald L Dalman
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Diseases ◽  
Myeloid Cells ◽  
Abdominal Aortic Aneurysms ◽  
Plasmacytoid Dendritic Cells ◽  
Aortic Aneurysms ◽  
Major Type ◽  
Abdominal Aortic

Introduction: Abdominal aortic aneurysms (AAA) manifest histologic features consistent with other chronic inflammatory diseases. Infiltrating mural myeloid cells (e.g. macrophages) are already recognized as important contributors to aneurysm pathogenesis, however, the role of plasmacytoid dendritic cells (pDC), major type 1 interferon-producing myeloid cells involving in autoimmune diseases and atherosclerosis, has not been previously investigated in this context. Methods and Results: AAAs were created in 12 week old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase (PPE). AAA development and progression were assessed via serial ultrasound determination of aortic diameter in vivo , and histology at sacrifice. The fraction of circulating leukocytes identified as pDCs was significantly increased immediately following PPE infusion (aneurysm initiation). Treatment with mPDCA-1 mAb (400 μg i.p. q.o.d.), beginning one day prior to PPE infusion, depleted more than 90% of bone marrow, spleen and peripheral blood pDCs (data not shown) and suppressed subsequent aneurysm development and progression compared to that noted in PPE-infused mice treated with control mAb. mPDCA-1 treatment promoted aortic medial elastin and smooth muscle preservation, while limiting mural macrophage accumulation and neocapillary formation. Conclusion: These findings suggest a role for plasmacytoid dendritic cells in promoting the initiation and progression of experimental abdominal aortic aneurysms.

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