Macrophage heterogeneity in myocardial infarction: Evolution and implications for diverse therapeutic approaches.

Given the extensive participation of myeloid cells (especially monocytes and macrophages) in both inflammation and resolution phases post-myocardial infarction (MI) owing to their biphasic role, these cells are considered as crucial players in the disease pathogenesis. Multiple studies have agreed on the significant contribution of macrophage polarization theory (M2 vs. M1) while determining the underlying reasons behind the observed biphasic effects; nevertheless, this simplistic classification attracts severe drawbacks.

Syndecan-4 as a genetic determinant of the metabolic syndrome.

Background: Syndecan-4 (SDC4) is a member of the heparan sulfate proteoglycan family of cell-surface receptors. We and others previously reported that variation in the SDC4 gene was associated with several components of the metabolic syndrome, including intra-abdominal fat, fasting glucose and triglyceride levels, and hypertension, in human cohorts. Additionally, we demonstrated that high fat diet (HFD)-induced obese female mice with a Sdc4 genetic deletion had higher visceral adiposity and a worse metabolic profile than control mice.

Immunological Insights into Cigarette Smoking-Induced Cardiovascular Disease Risk.

Smoking is one of the most prominent addictions of the modern world, and one of the leading preventable causes of death worldwide. Although the number of tobacco smokers is believed to be at a historic low, electronic cigarette use has been on a dramatic rise over the past decades. Used as a replacement for cigarette smoking, electronic cigarettes were thought to reduce the negative effects of burning tobacco.

Neutrophil Migratory Patterns: Implications for Cardiovascular Disease.

The body's inflammatory response involves a series of processes that are necessary for the immune system to mitigate threats from invading pathogens. Leukocyte migration is a crucial process in both homeostatic and inflammatory states. The mechanisms involved in immune cell recruitment to the site of inflammation are numerous and require several cascades and cues of activation.

Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow Is Essential for Myocardial Infarction-Induced Granulopoiesis.

Background: Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. This is mediated in part by granulopoiesis induced by the S100A8/A9-NLRP3-IL-1β signaling axis in injury-exposed neutrophils. Despite the transcriptional upregulation of the NLRP3 (Nod Like Receptor Family Pyrin Domain-Containing 3) inflammasome and associated signaling components in neutrophils, the serum levels of IL-1β (interleukin-1β), the effector molecule in granulopoiesis, were not affected by MI, suggesting that IL-1β is not released systemically.

Neutrophils in cardiovascular disease: warmongers, peacemakers, or both?

Neutrophils, the most abundant of all leucocytes and the first cells to arrive at the sites of sterile inflammation/injury act as a double-edged sword. On one hand, they inflict a significant collateral damage to the tissues and on the other hand, they help facilitate wound healing by a number of mechanisms. Recent studies have drastically changed the perception of neutrophils from being simple one-dimensional cells with an unrestrained mode of action to a cell type that display maturity and complex behaviour.

Oxidative Stress in Neutrophils: Implications for Diabetic Cardiovascular Complications.

Neutrophil behavior and function are altered by hyperglycemia associated with diabetes. Aberrant activation by hyperglycemia causes neutrophils to respond with increased production of reactive oxidative species (ROS). Excess ROS, a signature of primed neutrophils, can intracellularly induce neutrophils to undergo NETosis, flooding surrounding tissues with ROS and damage-associated molecular patterns such as S100 calcium binding proteins (S100A8/A9).

Apoptotic Ablation of Platelets Reduces Atherosclerosis in Mice With Diabetes.

Objective: People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis.

Origins and diversity of macrophages in health and disease.

Macrophages are the first immune cells in the developing embryo and have a central role in organ development, homeostasis, immunity and repair. Over the last century, our understanding of these cells has evolved from being thought of as simple phagocytic cells to master regulators involved in governing a myriad of cellular processes. A better appreciation of macrophage biology has been matched with a clearer understanding of their diverse origins and the flexibility of their metabolic and transcriptional machinery.

Emerging roles of neutrophil-borne S100A8/A9 in cardiovascular inflammation.

Elevated neutrophil count is associated with higher risk of major adverse cardiac events including myocardial infarction and early development of heart failure. Neutrophils contribute to cardiac damage through a number of mechanisms, including attraction of other immune cells and release of inflammatory mediators. Recently, a number of independent studies have reported a causal role for neutrophil-derived alarmins (i.

S100 family proteins in inflammation and beyond.

The S100 family proteins possess a variety of intracellular and extracellular functions. They interact with multiple receptors and signal transducers to regulate pathways that govern inflammation, cell differentiation, proliferation, energy metabolism, apoptosis, calcium homeostasis, cell cytoskeleton and microbial resistance. S100 proteins are also emerging as novel diagnostic markers for identifying and monitoring various diseases.

Attack of the NETs! NETosis primes IL-1β-mediated inflammation in diabetic foot ulcers.

In volume 133 issue 4 of Clinical Science, Liu et al. showed that neutrophils release extracellular traps (NETs) in the setting of diabetes which acts as a stimulus for NLRP3 inflammasome activation in macrophages to promote IL1β-dependent exacerbation of inflammation. They also provide evidence to show that degrading NETs improves the wound healing process.

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction.

Background: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.

Methods: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types.

Circulating stem cells and cardiovascular outcomes: from basic science to the clinic.

The cardiovascular and haematopoietic systems have fundamental inter-relationships during development, as well as in health and disease of the adult organism. Although haematopoietic stem cells (HSCs) emerge from a specialized haemogenic endothelium in the embryo, persistence of haemangioblasts in adulthood is debated. Rather, the vast majority of circulating stem cells (CSCs) is composed of bone marrow-derived HSCs and the downstream haematopoietic stem/progenitors (HSPCs).

The Art of Intercellular Wireless Communications: Exosomes in Heart Disease and Therapy.

Exosomes are nanoscale membrane-bound extracellular vesicles secreted by most eukaryotic cells in the body that facilitates intercellular communication. Exosomes carry several signaling biomolecules, including miRNA, proteins, enzymes, cell surface receptors, growth factors, cytokines and lipids that can modulate target cell biology and function. Due to these capabilities, exosomes have emerged as novel intercellular signaling mediators in both homeostasis and pathophysiological conditions.

Bone Marrow-Derived Cells Restore Functional Integrity of the Gut Epithelial and Vascular Barriers in a Model of Diabetes and ACE2 Deficiency.

Rationale: There is incomplete knowledge of the impact of bone marrow cells on the gut microbiome and gut barrier function.

Objective: We postulated that diabetes mellitus and systemic ACE2 (angiotensin-converting enzyme 2) deficiency would synergize to adversely impact both the microbiome and gut barrier function.

Methods And Results: Bacterial 16S rRNA sequencing and metatranscriptomic analysis were performed on fecal samples from wild-type, ACE2, Akita (type 1 diabetes mellitus), and ACE2-Akita mice.

S100A8/A9 in Myocardial Infarction.

S100A8/A9 represents a novel biomarker and therapeutic target in sterile inflammatory diseases. Among the various S100 proteins, S100A8 and S100A9 have been shown to be the most important of all the damage-associated molecular pattern (DAMP) proteins in sterile inflammatory conditions such as diabetes, cardiovascular disease, autoimmune disorders, etc. We present here methods to quantify S100A8/A9 expression in various tissues in mouse models of myocardial infarction (MI) using flow cytometry (FC), immunofluorescence, quantitative real-time polymerase chain reaction (q-RT-PCR), and enzyme-linked immunosorbent assays (ELISA).

The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury.

The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice.