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Platelets play a critical role In atherogenesis and thrombosis-mediated myocardial Ischemia, processes that are accelerated In diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium -glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes., Introduction Diabetes is a major risk factor for cardiovascular disease (CVD), which remains the leading cause of mortality worldwide (1-3). Atherosclerosis is the major underlying cause of CVD and is [...]

Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1β (IL-1β). We investigated whether inhibiting the NLRP3 inflammasome, through the use of the specific small-molecule NLRP3 inhibitor MCC950, could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis in the streptozotocin-induced diabetic apolipoprotein E-knockout mouse. Diabetes led to an approximately fourfold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (P < 0.001). This reduction in lesions was associated with decreased monocyte-macrophage content, reduced necrotic core, attenuated inflammatory gene expression (IL-1β, tumor necrosis factor-α, intracellular adhesion molecule 1, and MCP-1; P < 0.05), and reduced oxidative stress, while maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (P < 0.05). In a range of cell lines (murine bone marrow-derived macrophages, human monocytic THP-1 cells, phorbol 12-myristate 13-acetate-differentiated human macrophages, and aortic smooth muscle cells from humans with diabetes), MCC950 significantly reduced IL-1β and/or caspase-1 secretion and attenuated leukocyte-smooth muscle cell interactions under high glucose or lipopolysaccharide conditions. In summary, MCC950 reduces plaque development, promotes plaque stability, and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease. [ABSTRACT FROM AUTHOR]

Haematopoiesis, the process of blood production, can be altered during the initiation or progression of many diseases. Cardiovascular disease (CVD) has been shown to be heavily influenced by changes to the haematopoietic system, including the types and abundance of immune cells produced. It is now well established that innate immune cells are increased in people with CVD, and the mechanisms contributing to this can be vastly different depending on the risk factors or comorbidities present. Many of these changes begin at the level of the haematopoietic stem and progenitor cells (HSPCs) that reside in the bone marrow (BM). In general, the HSPCs and downstream myeloid progenitors are expanded via increased proliferation in the setting of atherosclerotic CVD. However, HSPCs can also be encouraged to leave the BM and colonise extramedullary sites (i.e. the spleen). Within the BM, HSPCs reside in specialized microenvironments, often referred to as a niche. To date in depth studies assessing the damage or dysregulation that occurs in the BM niche in varying CVDs are scarce. In this review, we provide a general overview of the complex components and interactions within the BM niche and how they influence the function of HSPCs. Additionally, we discuss the main findings regarding changes in the HSPC niche that influence the progression of CVD. We hypothesize that understanding the influence of the BM niche in CVD will aid in delineating new pathways for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aim: Rheumatoid arthritis (RA) is associated with an approximately two-fold elevated risk of cardiovascular (CV)-related mortality. Patients with RA present with systemic inflammation including raised circulating myeloid cells, but fail to display traditional CV risk-factors, particularly dyslipidaemia. We aimed to explore if increased circulating myeloid cells is associated with impaired atherosclerotic lesion regression or altered progression in RA. Methods and results: Using flow cytometry, we noted prominent monocytosis, neutrophilia, and thrombocytosis in two mouse models of RA. This was due to enhanced proliferation of the haematopoietic stem and progenitor cells (HSPCs) in the bone marrow and the spleen. HSPCs expansion was associated with an increase in the cholesterol content, due to a downregulation of cholesterol efflux genes, Apoe, Abca1, and Abcg1. The HSPCs also had enhanced expression of key myeloid promoting growth factor receptors. Systemic inflammation was found to cause defective cellular cholesterol metabolism. Increased myeloid cells in mice with RA were associated with a significant impairment in lesion regression, even though cholesterol levels were equivalent to non-arthritic mice. Lesions from arthritic mice exhibited a less stable phenotype as demonstrated by increased immune cell infiltration, lipid accumulation, and decreased collagen formation. In a progression model, we noted monocytosis, enhanced monocytes recruitment to lesions, and increased plaque macrophages. This was reversed with administration of reconstituted high-density lipoprotein (rHDL). Furthermore, RA patients have expanded CD16þ monocyte subsets and a down-regulation of ABCA1 and ABCG1. Conclusion: Rheumatoid arthritis impairs atherosclerotic regression and alters progression, which is associated with an expansion of myeloid cells and disturbed cellular cholesterol handling, independent of plasma cholesterol levels. Infusion of rHDL prevented enhanced myelopoiesis and monocyte entry into lesions. Targeting cellular cholesterol defects in people with RA, even if plasma cholesterol is within the normal range, may limit vascular disease. [ABSTRACT FROM AUTHOR]

Background and aims Monocyte levels predict cardiovascular outcomes and play a causal role in atherogenesis. Monocytes can be produced in the spleen and track to the atherosclerotic lesion in significant numbers. The cholinergic system has been shown to have anti-inflammatory actions in the spleen. We aimed to explore whether therapeutic stimulation of the nicotinic acetylcholine receptor alpha 7 (nAChRα7) can suppress atherogenesis. Methods Apoe −/− mice were placed on a Western-type diet and treated with bi-daily injections of the nAChRα7 agonist GTS-21 or vehicle every 2–3 days for 8 weeks. Results GTS-21 caused a reduction in atherosclerosis in the aortic arch and proximal aorta. This also resulted in less plaque macrophages. Moreover, GTS-21 reduced the abundance of blood monocytes, which was caused by inhibition of inflammatory cytokines and extramedullary hematopoiesis in the spleen, along with splenic monocytes. Conclusions Stimulation of nAChRα7 with GTS-21 reduced atherosclerosis, which was associated with dampened splenic myelopoiesis. [ABSTRACT FROM AUTHOR]

Background and Objectives Study Design and Methods Results Conclusion Reproductive‐aged women are at an increased risk of developing iron deficiency (ID). We aimed to develop a non‐invasive screening tool to identify ID in women and assess the acceptability of screening.We screened women (age 18–49 years) in the community of Western Australia. Primary outcome: acceptability of screening, assessed by the feasibility of recruiting the required sample size (n = 323). Secondary outcomes: Hand grip strength, finger prick haemoglobin concentration (Hb), prevalence of heavy menstrual bleeding (HMB), diet, pregnancy history, blood donation, symptoms of ID and history of ID or anaemia (Hb < 120 g/L). Those with Hb <130 g/L and no history of iron therapy in the past 2 years were given referrals for venous full blood count and ferritin sampling.Across 5 days, we recruited 640 eligible women. Of which, 178 (28%) had HMB and 79 (12%) were anaemic. Mean age was 33.5 ± 9.2 years, and mean Hb was 132.4 ± 11.9 g/L. In the past 2 years: 335 (52%) were diagnosed with ID or anaemia; 322 (50%) had taken oral iron; and 210 (33%) had an intravenous iron infusion. Vegetarian diets were followed by 89 (14%); 40 (6%) were regular blood donors; 290 (45%) had a previous pregnancy.HMB increased the risk of symptoms of ID and having prior ID/anaemia diagnosis (67% vs. 47%) or treatment (p < 0.022). Hand grip strength showed a positive relationship with both Hb (adjusted R2 = 0.012, p = 0.004) and ferritin (adjusted R2 = 0.135, p = 0.005).ID screening was well accepted by women in the community, with high recruitment rates over a short period. Future screening tool development may consider incorporating hand grip strength and HMB assessment. [ABSTRACT FROM AUTHOR]

Monocytes in humans consist of 3 subsets; CD14 + CD16 - (classical), CD14 + CD16 + (intermediate) and CD14 dim CD16 + (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14 + CD16 - monocytes are significantly elevated and migrate to the sites of injury via the adhesion cascade. The field of immunometabolism has begun to elucidate the importance of the engagement of specific metabolic pathways in immune cell function. Yet, little is known about monocyte metabolism and the role of metabolism in mediating monocyte activation and adherence to vessels. Accordingly, we aimed to determine whether manipulating the metabolism of CD14 + CD16 - monocytes alters their ability to become activated and adhere. We discovered that LPS stimulation increased the rate of glycolysis in human CD14 + CD16 - monocytes. Inhibition of glycolysis with 2-deoxy-D-glucose blunted LPS-induced activation and adhesion of monocytes. Mechanistically, we found that increased glycolysis was regulated by mTOR-induced glucose transporter (GLUT)-1. Furthermore, enhanced glycolysis increased accumulation of reactive oxygen species (ROS) and activation of p38 MAPK, which lead to activation and adhesion of monocytes. These findings reveal that glycolytic metabolism is critical for the activation of CD14 + CD16 - monocytes and contributes to our understanding of the interplay between metabolic substrate preference and immune cell function.

Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the β-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events., (Copyright© 2019 Ferrata Storti Foundation.)

Haematopoiesis, the process of blood production, can be altered during the initiation or progression of many diseases. Cardiovascular disease (CVD) has been shown to be heavily influenced by changes to the haematopoietic system, including the types and abundance of immune cells produced. It is now well established that innate immune cells are increased in people with CVD, and the mechanisms contributing to this can be vastly different depending on the risk factors or comorbidities present. Many of these changes begin at the level of the haematopoietic stem and progenitor cells (HSPCs) that reside in the bone marrow (BM). In general, the HSPCs and downstream myeloid progenitors are expanded via increased proliferation in the setting of atherosclerotic CVD. However, HSPCs can also be encouraged to leave the BM and colonise extramedullary sites (i.e. the spleen). Within the BM, HSPCs reside in specialized microenvironments, often referred to as a niche. To date in depth studies assessing the damage or dysregulation that occurs in the BM niche in varying CVDs are scarce. In this review, we provide a general overview of the complex components and interactions within the BM niche and how they influence the function of HSPCs. Additionally, we discuss the main findings regarding changes in the HSPC niche that influence the progression of CVD. We hypothesize that understanding the influence of the BM niche in CVD will aid in delineating new pathways for therapeutic interventions.