Inflammatory Cells and Proteases in Abdominal Aortic Aneurysm and its Complications

Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA.

Download Full-text

Abstract 260: Identification of Micrornas Specifically Expressed in Isolated Cells of Human Abdominal Aortic Aneurysm

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.260 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Florence Pinet ◽

Rafaelle Spear ◽

David Hot ◽

Bart Staels ◽

Maggy Chwastyniak ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Inflammatory Cells ◽

The Elderly ◽

M2 Macrophages ◽

Isolated Cells ◽

Human Mirnas ◽

Specific Distribution ◽

Abdominal Aortic ◽

M1 And M2 Macrophages

Abdominal aortic aneurysm (AAA) is a vascular asymptomatic disease responsible for 4% of mortality in the elderly population. MicroRNAs (miRNA) have recently been shown to be potential biomarkers due to their stability in plasma. The aim of this study was to investigate the potentiality of miRNAS as biomarkers of AAA by identifying miRNAs specifically expressed in the key cells present in the human AAA tissue. The distribution of inflammatory cells such as smooth muscle cells (SMC), M1 and M2 macrophages, neutrophils, B and T lymphocytes and mast cells were located by immunohistochemistry in 20 human AAA biopsies, showing a specific distribution towards the aneurysmal aortic wall and the presence of adventitial tertiary lymphoid organs (ATLOs) in 10 samples. We isolated by laser microdissection (LMD) area enriched in aneurysmal SMC, M1 and M2 macrophages, and ATLOs and SMC from control aorta. RNA extracted from 2 samples of LMD-isolated cells was screened on human miRNAs microarray. Out of the 850 human miRNAs, more than 200 miRNAs were detected in LMD-isolated aneurysmal cells, with 164 detected in ATLOs, 49 in SMC, and 87 miRNAs in macrophages. We selected the 3 miRs with the highest expression for ATLOs and 10 miRs (based on their miR-29b levels) for SMC and macrophages for validation by qRT-PCR in LMD-isolated samples (n=4). We found that miR-15a-3p (0.1 fold) and miR-30a-5p (0.2 fold) were down-regulated and miR-489-3p up-regulated (2 fold) in ATLOs which was inversed for miR-489-3p in the whole aneurysmal aorta. Of the 10 miRNAs selected, six (miR-199a-3p and miR-451 upregulated and miR-24, miR-29a, miR-29b, and miR-29c downregulated) were modulated similarly in SMC and macrophages and whole aneurysmal aorta, except for miR-199-3p. Let-7f and miR-34a were similarly upregulated ed in both subtypes of macrophages and aneurysmal aorta. Expression in the plasma of AAA (n=24) compared to PAD (n=18) patients was significantly down-regulated for miR-15a-3p (p = 0.03) and miR-30a-5p (p = 0.04) and upregulated for let-7f (p=0.048) and miR-29b (p=0.035). In conclusion, this non-hypothesis driven screening of miRNAs expressed in isolated aneurysmal cells allowed to identify four miRNAs as potential AAA biomarkers.

Download Full-text

A Novel Hypothesis: A Role for Follicle Stimulating Hormone in Abdominal Aortic Aneurysm Development in Postmenopausal Women

Frontiers in Endocrinology ◽

10.3389/fendo.2021.726107 ◽

2021 ◽

Vol 12 ◽

Author(s):

Victoria N. Tedjawirja ◽

Max Nieuwdorp ◽

Kak Khee Yeung ◽

Ron Balm ◽

Vivian de Waard

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Postmenopausal Women ◽

Cholesterol Biosynthesis ◽

Follicle Stimulating Hormone ◽

Inflammatory Cells ◽

Cell Types ◽

Menopausal Transition ◽

Abdominal Aortic ◽

Stimulating Hormone

An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta, which can potentially be fatal due to exsanguination following rupture. Although AAA is less prevalent in women, women with AAA have a more severe AAA progression compared to men as reflected by enhanced aneurysm growth rates and a higher rupture risk. Women are diagnosed with AAA at an older age than men, and in line with increased osteoporosis and cardiovascular events, the delayed AAA onset has been attributed to the reduction of the protective effect of oestrogens during the menopausal transition. However, new insights have shown that a high follicle stimulating hormone (FSH) level during menopause may also play a key role in those diseases. In this report we hypothesize that FSH may aggravate AAA development and progression in postmenopausal women via a direct and/or indirect role, promoting aorta pathology. Since FSH receptors (FSHR) are reported on many other cell types than granulosa cells in the ovaries, it is feasible that FSH stimulation of FSHR-bearing cells such as aortic endothelial cells or inflammatory cells, could promote AAA formation directly. Indirectly, AAA progression may be influenced by an FSH-mediated increase in osteoporosis, which is associated with aortic calcification. Also, an FSH-mediated decrease in cholesterol uptake by the liver and an increase in cholesterol biosynthesis will increase the cholesterol level in the circulation, and subsequently promote aortic atherosclerosis and inflammation. Lastly, FSH-induced adipogenesis may lead to obesity-mediated dysfunction of the microvasculature of the aorta and/or modulation of the periaortic adipose tissue. Thus the long term increased plasma FSH levels during the menopausal transition may contribute to enhanced AAA disease in menopausal women and could be a potential novel target for treatment to lower AAA-related events in women.

Download Full-text

Antithrombotic therapy in abdominal aortic aneurysm: beneficial or detrimental?

Blood ◽

10.1182/blood-2017-08-743237 ◽

2018 ◽

Vol 132 (25) ◽

pp. 2619-2628 ◽

Cited By ~ 6

Author(s):

Scott J. Cameron ◽

Hannah M. Russell ◽

A. Phillip Owens

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Aortic Rupture ◽

Complex Structure ◽

Treatment Strategies ◽

Inflammatory Cells ◽

Vascular Pathology ◽

Coagulation Cascade ◽

Abdominal Aortic

Abstract Abdominal aortic aneurysm (AAA) is a degenerative vascular pathology resulting in significant morbidity and mortality in older adults due to rupture and sudden death. Despite 150 000 new cases and nearly 15 000 deaths annually, the only approved treatment of AAA is surgical or endovascular intervention when the risk for aortic rupture is increased. The goal of the scientific community is to develop novel pharmaceutical treatment strategies to reduce the need for surgical intervention. Because most clinically relevant AAAs contain a complex structure of fibrin, inflammatory cells, platelets, and red blood cells in the aneurysmal sac known as an intraluminal thrombus (ILT), antithrombotic therapies have emerged as potential pharmaceutical agents for the treatment of AAA progression. However, the efficacy of these treatments has not been shown, and the effects of shrinking the ILT may be as detrimental as they are beneficial. This review discusses the prospect of anticoagulant and antiplatelet (termed collectively as antithrombotic) therapies in AAA. Herein, we discuss the role of the coagulation cascade and platelet activation in human and animal models of AAA, the composition of ILT in AAA, a possible role of the ILT in aneurysm stabilization, and the implications of antithrombotic drugs in AAA treatment.

Download Full-text

Depletion of CD11c+ cell attenuates progression of abdominal aortic aneurysm

Clinical Science ◽

10.1042/cs20191083 ◽

2020 ◽

Vol 134 (1) ◽

pp. 33-37

Author(s):

Keisuke Okuno ◽

Stephanie Cicalese ◽

Satoru Eguchi

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Arterial Wall ◽

Inflammatory Cells ◽

Matrix Remodeling ◽

Lower Plasma ◽

Elastase Activity ◽

Abdominal Aortic ◽

Underlying Mechanisms ◽

Therapeutic Research

Abstract Chronic inflammation of the arterial wall has been implicated in the development of abdominal aortic aneurysm (AAA). However, the detailed molecular mechanism(s) by which inflammatory cells contributes to AAA pathogenesis remains largely unclear. In their article in Clinical Science, Krishna et al. have reported that depletion of CD11c+ dendritic cells inhibited experimental AAA formation in mice. The authors also demonstrated a decrease in CD4 and CD8 positive T cells in the circulation, lower plasma neutrophil elastase activity, and aortic matrix remodeling. These novel findings will help clarify the underlying mechanisms of AAA progression and may provide a new target for future therapeutic research in AAA formation.

Download Full-text

Myeloid-Derived TSP1 (Thrombospondin-1) Contributes to Abdominal Aortic Aneurysm Through Suppressing Tissue Inhibitor of Metalloproteinases-1

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314913 ◽

2020 ◽

Vol 40 (12) ◽

Author(s):

Huan Yang ◽

Ting Zhou ◽

Christine M. Sorenson ◽

Nader Sheibani ◽

Bo Liu

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Molecular Mechanisms ◽

Inflammatory Cells ◽

Matricellular Protein ◽

Tissue Inhibitor Of Metalloproteinases ◽

Tissue Inhibitor ◽

Abdominal Aortic ◽

Thrombospondin 1 ◽

Inflammatory Macrophages

Objective: Abdominal aortic aneurysm is characterized by the progressive loss of aortic integrity and accumulation of inflammatory cells primarily macrophages. We previously reported that global deletion of matricellular protein TSP1 (thrombospondin-1) protects mice from aneurysm formation. The objective of the current study is to investigate the cellular and molecular mechanisms underlying TSP1’s action in aneurysm. Approach and Results: Using RNA fluorescent in situ hybridization, we identified macrophages being the major source of TSP1 in human and mouse aneurysmal tissues, accounting for over 70% of cells that actively expressed Thbs1 mRNA. Lack of TSP1 in macrophages decreased solution-based gelatinase activities by elevating TIMP1 (tissue inhibitor of metalloproteinases-1) without affecting the major MMPs (matrix metalloproteinases). Knocking down Timp1 restored the ability of Thbs1 − /− macrophages to invade matrix. Finally, we generated Thbs1 flox/flox mice and crossed them with Lyz2-cre mice. In the CaCl 2 -induced model of abdominal aortic aneurysm, lacking TSP1 in myeloid cells was sufficient to protect mice from aneurysm by reducing macrophage accumulation and preserving aortic integrity. Conclusions: TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.

Download Full-text

Cathepsin S is associated with degradation of collagen I in abdominal aortic aneurysm

VASA ◽

10.1024/0301-1526/a000701 ◽

2018 ◽

Vol 47 (4) ◽

pp. 285-293 ◽

Cited By ~ 5

Author(s):

Veronika Klaus ◽

Fadwa Schmies ◽

Christian Reeps ◽

Matthias Trenner ◽

Sarah Geisbüsch ◽

...

Keyword(s):

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Heavy Chain ◽

Protein Level ◽

Mrna Level ◽

Inflammatory Cells ◽

Collagen I ◽

Cathepsin S ◽

Abdominal Aortic

Abstract. Background: Cathepsins have been described in the pathogenesis of abdominal aortic aneurysm (AAA), their exact role, especially in collagen degradation, is still unclear. The aim of the present study was therefore to analyse relevant cathepsins in human AAA tissue samples in relation to collagen I, III, and their degradation products. Materials and methods: Samples from 37 AAA patients obtained from elective open surgical repair and eight healthy non-aneurysmatic aortas from kidney donors were included. Expression of cathepsins B, D, K, L, S, cystatin C, collagen I and III, their degraded products C-Telopeptide of type 1 and 3 collagen (CTX-I, CTX-III), cellular markers for leukocytes (CD45), T cells (CD3), macrophage scavenger receptor-1 (MSR-1), synthetic, and contractile smooth muscle cells (SMCs) (smoothelin: SMTH, collagen I and III, myosin heavy chain: MHC, embryonic smooth muscle myosin heavy chain: SMemb) were determined at messenger RNA (mRNA) level, using SYBRGreen-based quantitative PCR and at protein level using enzyme-linked immunosorbent assay (ELISA). Results: Expression of cathepsins B, D, L, and S at mRNA level was significantly elevated in AAA compared to control aorta (1.7-fold, p = 0.025; 2.5-fold, p = 0.002; 2.6-fold, p = 0.034; and 7.0-fold, p = 0.003). Expression of cathepsin S correlated significantly with leukocytes and macrophages (ρ = 0.398, p = 0.033 and ρ = 0.422, p = 0.020), synthetic SMCs were significantly associated with cathepsins B, D, and L (ρ = 0.522, p = 0.003; ρ = 0.431, p = 0.015 and ρ = 0.467, p = 0.008). At protein level, cathepsins B and S were elevated in AAA compared to controls (5.4-fold, p = 0.001 and 7.3-fold, p < 0.001). Significant correlations were observed between collagen I, its degraded product, and cathepsin S (r = –0.350, p = 0.034 and r = +0.504, p < 0.001). Expression of cathepsin B was associated with SMCs, expression of cathepsin S with inflammatory cells. Conclusions: Particularly cathepsin S was associated with the degradation product of collagen I and thus might be involved in the progression of AAA. Furthermore, cathepsin S correlated with inflammatory cells.

Download Full-text

Modulation of Immune-Inflammatory Responses in Abdominal Aortic Aneurysm: Emerging Molecular Targets

Journal of Immunology Research ◽

10.1155/2018/7213760 ◽

2018 ◽

Vol 2018 ◽

pp. 1-15 ◽

Cited By ~ 21

Author(s):

Hanrong Li ◽

Shuling Bai ◽

Qiang Ao ◽

Xiaohong Wang ◽

Xiaohong Tian ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Immune System ◽

Aortic Aneurysm ◽

Innate Immune System ◽

Chemokine Receptors ◽

Inflammatory Cell ◽

Inflammatory Responses ◽

Inflammatory Cells ◽

Innate Immune ◽

Abdominal Aortic

Abdominal aortic aneurysm (AAA), a deadly vascular disease in human, is a chronic degenerative process of the abdominal aorta. In this process, inflammatory responses and immune system work efficiently by inflammatory cell attraction, proinflammatory factor secretion and subsequently MMP upregulation. Previous studies have demonstrated various inflammatory cell types in AAA of human and animals. The majority of cells, such as macrophages, CD4+ T cells, and B cells, play an important role in the diseased aortic wall through phenotypic modulation. Furthermore, immunoglobulins also greatly affect the functions and differentiation of immune cells in AAA. Recent evidence suggests that innate immune system, especially Toll-like receptors, chemokine receptors, and complements are involved in the progression of AAAs. We discussed the innate immune system, inflammatory cells, immunoglobulins, immune-mediated mechanisms, and key cytokines in the pathogenesis of AAA and particularly emphasis on a further trend and application of these interventions. This current understanding may offer new insights into the role of inflammation and immune response in AAA.

Download Full-text

Salmonellosis associated with abdominal aortic aneurysm

Archives of Internal Medicine ◽

10.1001/archinte.134.6.1095 ◽

1974 ◽

Vol 134 (6) ◽

pp. 1095-1098 ◽

Cited By ~ 5

Author(s):

Y. S. Kanwar

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Abdominal Aortic

Download Full-text

Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽

10.1024/0301-1526.34.4.217 ◽

2005 ◽

Vol 34 (4) ◽

pp. 217-223 ◽

Cited By ~ 11

Author(s):

Diehm ◽

Schmidli ◽

Dai-Do ◽

Baumgartner

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Medical Treatment ◽

Endovascular Treatment ◽

Abdominal Aortic Aneurysms ◽

Aortic Aneurysms ◽

Current Evidence ◽

Significant Morbidity ◽

Abdominal Aortic ◽

Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

Download Full-text