Juliette Raffort

Micro-RNAs in abdominal aortic aneurysms: insights from animal models and relevance to human disease

Abdominal aortic aneurysm (AAA) is a major health concern and may be associated with high rates of mortality linked to acute complications. Diagnosis and treatment are, respectively, based on imaging and surgical techniques. Drug-based therapies are still mostly ineffective, which highlight a real unmet need. Major pathophysiological mechanisms leading to aneurysm formation involve inflammatory processes, degradation of the extracellular matrix, and loss of smooth muscle cells. However, the precise cellular and molecular pathways are still poorly understood. Recently, microRNAs have emerged as major intracellular players in a wide range of biological processes, and their stability in extracellular medium within microvesicles has led to propose them as mediators of intercellular crosstalk and as potential biomarkers and therapeutic targets in a variety of disease settings. To date, several studies have been performed to address the involvement of micro-RNAs (miRs) in aneurysm formation and complications. Here, we discuss the roles and implications of miRs in animal models and their relevance to human AAA.

Monocytes and macrophages in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity, and high mortality in the event of aortic rupture. Major advances in open surgical and endovascular repair of AAA have been achieved during the past 2 decades. However, drug-based therapies are still lacking, highlighting a real need for better understanding of the molecular and cellular mechanisms involved in AAA formation and progression. The main pathological features of AAA include extracellular matrix remodelling associated with degeneration and loss of vascular smooth muscle cells and accumulation and activation of inflammatory cells. The inflammatory process has a crucial role in AAA and substantially influences many determinants of aortic wall remodelling. In this Review, we focus specifically on the involvement of monocytes and macrophages, summarizing current knowledge on the roles, origin, and functions of these cells in AAA development and its complications. Furthermore, we show and propose that distinct monocyte and macrophage subsets have critical and differential roles in initiation, progression, and healing of the aneurysmal process. On the basis of experimental and clinical studies, we review potential translational applications to detect, assess, and image macrophage subsets in AAA, and discuss the relevance of these applications for clinical practice.

Marginal zone B cells control the response of follicular helper T cells to a high-cholesterol diet

Splenic marginal zone B (MZB) cells, positioned at the interface between circulating blood and lymphoid tissue, detect and respond to blood-borne antigens. Here we show that MZB cells in mice activate a homeostatic program in response to a high-cholesterol diet (HCD) and regulate both the differentiation and accumulation of T follicular helper (TFH) cells. Feeding mice an HCD resulted in upregulated MZB cell surface expression of the immunoregulatory ligand PDL1 in an ATF3-dependent manner and increased the interaction between MZB cells and pre-TFH cells, leading to PDL1-mediated suppression of TFH cell motility, alteration of TFH cell differentiation, reduced TFH abundance and suppression of the proatherogenic TFH response. Our findings reveal a previously unsuspected role for MZB cells in controlling the TFH–germinal center response to a cholesterol-rich diet and uncover a PDL1-dependent mechanism through which MZB cells use their innate immune properties to limit an exaggerated adaptive immune response.

TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm

Objective— Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGF&bgr; (transforming growth factor-&bgr;) activity—a guardian of vascular integrity and immune homeostasis—would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. Approach and Results— Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGF&bgr; using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGF&bgr; blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1&bgr; or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1&bgr; after disease initiation has no effect on AAA progression to rupture. Conclusions— Endogenous TGF&bgr; activity is required for the healing of AAA. TGF&bgr; blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.

High Neutrophil to Lymphocyte Ratio Is Associated With Symptomatic and Ruptured Thoracic Aortic Aneurysm

The predictive value of the neutrophil to lymphocyte ratio (NLR) has been demonstrated in several cardiovascular diseases. The aim of our study was to investigate the association between the preoperative NLR and aneurysm characteristics as well as 30-day postoperative morbidity and mortality in patients with thoracic aortic aneurysm (TAA) undergoing aortic surgical repair. Consecutive patients (n = 75) with TAA were retrospectively included over a 10-year period. Clinical characteristics, aneurysm characteristics, and 30-day postoperative outcome were recorded. The median age of patients was 71 (67-80) years. The median preoperative NLR was 3.5 (2.3-5.8). The proportion of asymptomatic TAA was significantly lower in patients with an NLR > 3.5 compared with those with an NLR < 3.5 (52.6% vs 75.7%; P = .054). The proportion of patients with pain or with ruptured TAA was significantly higher in patients with an NLR > 3.5 compared with those with NLR < 3.5 (42.1% vs 16.2%; P = .022 and 26.3% vs 2.7%; P = .007, respectively). No significant difference was observed regarding the 30-day overall postoperative mortality and morbidity. The preoperative NLR did not correlate with TAA diameter. A high preoperative NLR is significantly associated with symptomatic and ruptured TAA, suggesting a potential interest as a marker and/or player in the disease.

Insights on glicentin, a promising peptide of the proglucagon family

Glicentin is a proglucagon-derived peptide mainly produced in the L-intestinal cells. While the roles of other members of the proglucagon family including glucagon-like peptide 1, glucagon-like peptide 2 and oxyntomodulin has been well studied, the functions and variation of glicentin in human are not fully understood. Experimental and clinical studies have highlighted its role in both intestinal physiology and glucose metabolism, pointing to its potential interest in a wide range of pathological states including gastrointestinal and metabolic disorders. Due to its structure presenting many similarities with the other proglucagon-derived peptides, its measurement is technically challenging. The recent commercialization of specific detection methods has offered new opportunities to go further in the understanding of glicentin physiology. Here we summarize the current knowledge on glicentin biogenesis and physiological roles. In the limelight of clinical studies investigating glicentin variation in human, we discuss future directions for potential applications in clinical practice.

Regarding ‘Diabetes mellitus increases the risk of ruptured abdominal aortic aneurysms’

Abdominal aortic aneurysm (AAA) is a life-threatening disease, associated with high rates of mortality in case of aortic rupture. While the disease is often associated with atherosclerosis and cardiovascular risk factors, the majority of epidemiological studies published so far have highlighted a negative association between diabetes and AAA. However, a recent publication from epidemiological data of the National Health Fund in Poland reported a higher incidence of AAA and rupture in diabetic patients compared to non-diabetics. Here, we discuss issues and methodological considerations hoping to shed light on these unexpected results.

Association of Platelet to Lymphocyte Ratio and Risk of 30-Day Postoperative Complications in Patients Undergoing Abdominal Aortic Surgical Repair

Introduction: The predictive value of the platelet to lymphocyte ratio (PLR) has been demonstrated in several cardiovascular diseases. The aim of this study was to investigate the interest of the preoperative PLR as a predictor of 30-day postoperative outcome in patients with abdominal aortic aneurysm (AAA) undergoing open or endovascular surgical repair. Material and Methods: Two hundred twenty-four consecutive patients with infrarenal AAA were retrospectively included and divided into 4 quartiles according to the value of the preoperative PLR: PLR < 91.5 (group I), 91.5 < PLR < 120.8 (group II), 120.8 < PLR < 163.3 (group III), and PLR > 163.3 (group IV). Results: The AAA diameter was similar among the groups (54.9 mm vs 58.6, 57.5, and 58.7 mm; P = .4655). The proportion of symptomatic AAA and the procedural characteristics did not differ. Patients from group I and IV had significantly higher rates of all-cause postoperative complications compared to group II and III (55.4% and 64.3% vs 39.3% and 46.4%, respectively; P = .0478). The all-cause mortality tended to be higher in group I and IV (7.1% and 8.9% vs 0% and 3.6%, respectively; P = .1305). Conclusion: Extreme values of PLR are associated with a higher risk of complications following AAA surgical repair, suggesting its interest as a biomarker to evaluate the surgical risk.

Investigation of Plasma Inflammatory Profile in Diabetic Patients With Abdominal Aortic Aneurysm: A Pilot Study

Introduction: Clinical studies have unraveled a negative association between diabetes and abdominal aortic aneurysm (AAA), but the mechanisms involved are still poorly understood. The aim of this study was to determine whether diabetic patients with AAA had a distinct plasma inflammatory profile compared to nondiabetic patients. Methods: Plasma samples were obtained from 10 diabetic patients with AAA and 10 nondiabetic patients with AAA. The relative protein expression of 92 inflammatory-related human protein biomarkers was assessed by proximity extension assay technology using Proseek Multiplex Inflammation I kit (Olink). Results: Clinical characteristics were similar in diabetic patients with AAA compared to nondiabetic patients with AAA, the median ages being 67 and 73 years, respectively (P = .61). The AAA diameters were, respectively, 50 and 49 mm (P = .72). Among the 92 markers screened, 67 (72.8%) were detected in all samples. Diabetic patients had significantly lower protein expression of C-C motif chemokine 19 (CCL19) and C-C motif chemokine 23 (CCL23; 542.3 vs 980.3, P = .01 and 1236 vs 1406, P = .04, respectively). They tended to have higher expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14) compared to controls (14.6 vs 10.8, P = .05). Conclusion: Diabetic patients with AAA differentially expressed CCL19, CCL23 and TNFSF14 in plasma compared to nondiabetic patients with AAA. Further studies are required to determine whether the markers identified could play a role in the negative association between diabetes and AAA pathogenesis.

Deletion of IRF8 (Interferon Regulatory Factor 8)-Dependent Dendritic Cells Abrogates Proatherogenic Adaptive Immunity.

Rationale: Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood. Objective: Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8&agr;+ and their developmentally related nonlymphoid CD103+ DCs) in the induction of proatherogenic immune responses during high fat feeding. Methods and Results: Using a fate-mapping technique to track DCs originating from a DNGR1+ (dendritic cell natural killer lectin group receptor 1) precursor (Clec9a+/creRosa+/EYFP mice), we first show that YFPhiCD11chiMHCIIhi (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor–deficient (Ldlr−/−) mice and are CD11b–CD103+IRF8hi. Restricted deletion of IRF8 in DCs (Irf8flox/floxCd11cCre) reduces the accumulation of CD11chiMHCIIhi DCs in the aorta without affecting CD11b+CD103– DCs or macrophages but completely abolishes the accumulation of aortic CD11b–CD103+ DCs. Lymphoid CD8&agr;+ DCs are also deleted. This is associated with a significant reduction of aortic T-cell accumulation and a marked reduction of high-fat diet–induced systemic T-cell priming, activation, and differentiation toward T helper type 1 cells, T follicular helper cells, and regulatory T cells. As a consequence, B-cell activation and germinal center responses to high-fat diet are also markedly reduced. IRF8 deletion in DCs significantly reduces the development of atherosclerosis, predominantly in the aortic sinus, despite a modest increase in total plasma cholesterol levels. Conclusions: IRF8 expression in DCs plays a nonredundant role in the development of proatherogenic adaptive immunity.