Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Sarcoidosis is a chronic inflammatory disease of unknown cause that can affect the heart and blood vessels, causing cardiomyopathy, pulmonary hypertension, and vasculitis. The pathological hallmark of sarcoidosis is the formation of noncaseating granulomas consisting of monocytes and dendritic cells, macrophages, multinucleated giant cells, and T cells. Sarcoidosis has features of autoimmune disease, and many candidate self-epitopes have been identified, but experimental validation is lacking. There is a strong hereditary component associated with the human leukocyte antigen region on chromosome 6. Symptoms of the disease may be subtle and often go unrecognized by patients and practitioners. Catastrophic events, including sudden cardiac death caused by lethal arrhythmias, can be the initial manifestation of the disease. Diagnosis is challenging and limited by the lack of sensitive and specific diagnostic tools, which also hampers monitoring of disease activity. Here, we discuss the cardiovascular manifestations and underlying immunobiology of sarcoidosis. We also review current diagnostic and treatment approaches for cardiac sarcoidosis, as well as the challenges faced by patients and clinicians and opportunities for future research.

Efferocytosis, the process by which phagocytes clear apoptotic cells, is essential for tissue homeostasis, inflammation resolution, and repair. Once considered a passive waste-disposal process, efferocytosis is now recognized as a dynamic, immunometabolic program that integrates apoptotic cell clearance with metabolic reprogramming and inflammation resolution. In cardiovascular contexts, efficient efferocytosis limits necrosis, enhances the deposition of wound healing matrix proteins, and promotes tissue healing, whereas impaired clearance drives chronic inflammation and maladaptive tissue remodeling. We review the molecular mechanisms governing efferocytosis, including the interplay of find-me, eat-me, and don't-eat-me signals with receptor-mediated cytoskeletal remodeling and lysosomal degradation. We highlight how efferocytosis drives lipid efflux, fatty acid oxidation, amino acid catabolism, and nucleotide recycling, processes that sustain continual efferocytosis and resolution programming. Defects in these pathways, amplified by proteolytic cleavage of apoptotic cell receptors, dysregulated metabolism, and inflammatory mediators, underlie impaired efferocytosis in atherosclerosis, myocardial infarction, vascular aging, and metabolic diseases. Finally, we discuss emerging concepts, including nonprofessional phagocyte contributions, crosstalk with adaptive immunity, and therapeutic strategies to enhance efferocytosis or preserve receptor integrity. Collectively, these insights redefine efferocytosis as more than a cleanup mechanism, positioning it as a central contributor to attenuating cardiometabolic diseases.

Viral hemorrhagic fever (VHF) describes different diseases caused by several viruses from 6 virus families: Filoviridae, Nairoviridae, Phenuiviridae, Hepadnaviridae, Arenaviridae, and Flaviviridae. VHF was once considered a geographically localized problem, but, due to expanding vector ranges and increased human contact with animal reservoirs and hosts, the number of VHF cases is increasing. As the name indicates, VHF is associated with bleeding. Both direct effects from viral infection of host cells and indirect effects caused by the host response to the virus contribute to the dysregulation of the hemostatic system. Many studies have measured different parameters and various biomarkers in samples from infected humans and nonhuman primate models. For example, Ebola virus infection in a nonhuman primate model leads to increased TF (tissue factor) expression in peripheral blood mononuclear cells and extracellular vesicles. In dengue virus infection, thrombocytopenia and platelet dysfunction occur. There are likely both common and distinct mechanisms underlying bleeding in different VHFs, as sites of bleeding differ between the viruses. Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability. While a significant body of work exists examining different aspects of the various viral infections that may lead to bleeding, there are still many open questions and areas for investigation. Therefore, more studies are needed to better understand the mechanisms underlying bleeding in VHF caused by different viruses.

C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally developed for the treatment of hereditary angioedema associated with C1INH deficiency. A growing body of literature indicates that C1INH products may find utility in the management of several other disease states. In this review, we detail the key biological activities of C1INH and consider the pathophysiological role of C1INH targets in many conditions. The therapeutic potential of exogenous C1INH is highlighted in the settings of thromboembolism, ischemia-reperfusion injury, sepsis, transplantation, and coronavirus disease 2019.

Zebrafish possess a remarkable capacity to regenerate cardiac tissues after injury, offering a powerful model to dissect the cellular and molecular mechanisms driving heart regeneration. Immune cells play distinct and context-dependent roles during regeneration, from debris clearance and inflammation resolution to modulation of cell proliferation and fibrosis. Here, we review the distinct contributions of neutrophils, macrophages, and lymphoid cells during zebrafish heart regeneration, with a focus on their temporal coordination and regulatory signaling pathways. Understanding proregenerative immune-mediated mechanisms may identify therapeutic targets to enhance cardiac repair in disease contexts, such as myocardial infarction and heart failure.

Background: Ischemic heart disease is the leading cause of mortality and human suffering globally. It often leaves patients with residual symptomatic burden despite current optimized procedural and medical options. Sotagliflozin, a dual SGLT1/2 (sodium-glucose cotransporter 1 and 2) inhibitor, has emerged for its clinically evident ischemic cardiovascular benefits. We hypothesize that sotagliflozin treatment exerts direct myocardial benefits in ischemic heart disease, independent of comorbid conditions.

Methods: Yorkshire swine (n=22) underwent placement of an ameroid constrictor around the left circumflex coronary artery. Following a 2-week period in which the ameroid gradually closes, swine (n=18) were randomized to receive either 400 mg daily sotagliflozin (n=8) or no drug (n=10) for 5 weeks. Afterwards, swine underwent terminal harvest to acquire cardiac functional data with pressure-volume loops, myocardial perfusion by microsphere injection, and ventricular sectioning. To investigate the cellular and tissue-level impact of therapy, histology, immunoblotting, and high-throughput techniques were performed.

Results: Sotagliflozin swine had improved ejection fraction, cardiac output, and stroke work compared with no drug (P<0.05) and a reduction in tau (P=0.04). Absolute blood flow to the ischemic myocardium was increased in the sotagliflozin group (P=0.03). Sotagliflozin swine had a reduction in 3-nitrotyrosine and trichrome staining, representing decreased reactive nitrogen species and myocardial fibrosis (P=0.03 for both). Molecularly, sotagliflozin swine demonstrated increased expression of endothelial nitric oxide synthase and superoxide dismutase 3 (P=0.02, P=0.04; respectively), with upregulated arginine metabolism, protein kinase A/cyclic adenosine monophosphate signaling, as well as glycolysis, fatty acid oxidation, and citric acid cycle.

Conclusions: Sotagliflozin treatment improved left ventricular function, myocardial perfusion, and diastolic relaxation, likely through reduced nitrosative stress and myocardial fibrosis, improved nitric oxide coupling, enhanced insulin signaling, and favorable metabolic shifts. This study suggests a potential role for sotagliflozin as a cardioprotective therapy in patients with ischemic heart disease beyond current treatment strategies.

Background: Medial arterial calcification is a common lesion associated with aging, chronic kidney disease, and diabetes that can lead to poor outcomes. Because the calcification is extensive when first apparent clinically or even radiologically, optimal therapy should target reversal in addition to prevention. However, studies to date suggest that medial calcification is irreversible under physiological conditions. This lack of reversal was investigated further by implanting calcified human arteries or hydroxyapatite subcutaneously into mice, or culturing them with murine osteoclasts in vitro.

Methods: Calcified human tibial arteries, obtained from amputations and previously frozen, were implanted subcutaneously in the dorsum of mice. Mineral content was measured by microcomputed tomography before and after implantation and compared with the calcium content of implanted pure hydroxyapatite or murine bone particles, along with histology. Calcified arteries were also incubated in vitro with osteoclasts generated by treating murine macrophages with receptor activator of NF-κB (nuclear factor kappa B).

Results: There was no decrease in mineral content of implanted arteries over 6 weeks and only minimal loss of calcium in devitalized bone particles, compared with almost complete resorption of hydroxyapatite. No resorption of hydroxyapatite occurred when implanted within a cell-impermeable diffusion chamber. Multinucleated giant cells, negative for osteoclast markers, were numerous among implanted hydroxyapatite, but rare in implanted arteries and bone. There was no histological evidence of resorption in calcified arteries incubated with osteoclasts.

Conclusions: Hydroxyapatite is readily reabsorbed in vivo by a cell-mediated process not involving osteoclasts. The lack of resorption of medial arterial calcifications, even in the presence of osteoclasts, indicates that calcifications have properties that prevent cell-mediated resorption. Further studies are needed to identify these properties and develop strategies to overcome this.

Advances in cancer therapies have transformed many malignancies into chronic or manageable conditions, but these treatments have been linked to adverse events. Vascular toxicities associated with cancer treatment range from abnormal vasoreactivity to accelerated atherosclerosis, arterial thrombotic events, vasculitis, and arterial aneurysms or dissections. 5-fluorouracil and VEGF (vascular endothelial growth factor) inhibitors are the agents most commonly linked to abnormal vasoreactivity, whereas BCR-ABL (breakpoint cluster region-Abelson murine leukemia viral oncogene homolog) inhibitors and immune checkpoint inhibitors have been associated with accelerated atherosclerosis. Arterial thrombotic events are seen with VEGF and BCR-ABL inhibitors as well as platinum drugs. Vasculitis emerged with the use of immune checkpoint inhibitors, and arterial aneurysms and dissections with VEGF inhibitors. Radiation therapy can lead to several of the outlined vascular toxicities. This review comprehensively explores the mechanisms of vascular complications associated with chemotherapy, targeted therapies, immunotherapies, and radiation therapy. Key contributors include endothelial injury and dysfunction, oxidative stress, and inflammation. An understanding of the mechanisms of vascular toxicities may facilitate optimal treatment and preventive strategies in patients with cancer.

Background: The application or excessive exposure to glucocorticoids constitutes a common adverse factor endured by intrauterine fetuses. Gestational glucocorticoids' exposure is intimately associated with the risk of postnatal vascular problems; however, whether the vascular problem can be transgenerationally inherited remains indistinct. In this study, a mouse model of gestational glucocorticoids' exposure was established, aiming to discover the abnormal phenotype of acquired vascular function of the offspring and clarify the epigenetic mechanism of the transgenerational transmission of the relevant abnormal phenotypes.

Methods: To model gestational glucocorticoid exposure, pregnant mice received intraperitoneal injections of dexamethasone (a synthetic glucocorticoid) on gestational days 12, 14, 16, and 18. Male offspring (F1) derived from dexamethasone group-exposed pregnancies were bred with wild-type females to generate F2 progeny, and this breeding strategy was repeated to produce F3 offspring. Adult male offspring from all 3 generations were subsequently analyzed.

Results: We observed that gestational dexamethasone group exposure induced a modest but consistent elevation in systolic blood pressure across F1 to F3 male offspring, accompanied by enhanced Ang II (angiotensin II)-mediated vascular contractility. Mechanistically, dexamethasone group exposure significantly reduced DNA methylation in the Agtr1a (Ang II receptor subtype A) gene promoter within F1 offspring vasculature, leading to upregulated Agtr1a expression and heightened oxidative stress via the AT1R (Ang II receptor 1)/NOX (nicotinamide adenine dinucleotide phosphate oxidase) 2/reactive oxygen species axis. This cascade potentiated Ang II-induced vascular contractility. Moreover, these acquired abnormal vascular problems can be stably inherited and transgenerationally transmitted through the alteration of the DNA methylation pattern of the Agtr1a gene in sperm.

Conclusions: This study demonstrates that gestational glucocorticoids' exposure triggers transgenerational inheritance of vascular dysfunction in male offspring via DNA methylation reprogramming, providing direct evidence for the epigenetic transmission of acquired traits. These findings advance our understanding of intergenerational disease mechanisms and offer novel insights for clinical strategies aimed at mitigating the adverse effects of gestational glucocorticoid therapy.

The delivery of insulin to the skeletal muscle has a major influence on glucose disposal in muscle, where 80% of total body glucose disposal occurs. The skeletal muscle microvascular endothelial cells play a critical role in peripheral insulin sensitivity through their regulation of insulin delivery. Recent advancements in methodologies have provided in-depth views of the molecular mechanisms by which the endothelial cells regulate the delivery process. However, how the cellular machinery is modulated under physiological or pathological conditions remains largely unexplored. Conditions with estrogen deficiency and obesity are 2 situations that are closely associated with peripheral insulin resistance and type 2 diabetes in humans. It is of great interest to determine whether and how endothelial control of insulin delivery impacts the development of metabolic dysregulation under these and other conditions. This review aims to provide an overview of the molecular mechanisms governing insulin delivery to the skeletal muscle. The available evidence will be presented that the transcytosis of insulin across the endothelial cell monolayer in skeletal muscle plays a critical role in muscle insulin delivery, thereby having a major impact on overall glucose homeostasis. In vivo investigations with manipulation of mechanisms in endothelial cells will be summarized, and the current knowledge gaps will be presented. Interrogation of the role of the endothelium in insulin transport provides a paradigm in which insights are being gained about cellular actions of insulin, molecular transport by endothelial cells, and the intricacies of glucose homeostasis.