Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Innate immune cells can develop a long-lasting hyperresponsive phenotype by metabolic and epigenetic reprogramming after brief exposure to inflammatory stimuli. Several experimental studies convincingly demonstrated that this immunologic phenomenon, which is called trained immunity, can accelerate the development of atherosclerosis. In this brief review, we summarize current evidence that diets and specific dietary components can modulate trained immunity. In mice, intermittent high-fat diets can reprogram bone marrow myeloid progenitor cells, resulting in hyperinflammatory monocytes and neutrophils that aggravate atherosclerosis. Diet-induced obesity also leads to persistent proinflammatory epigenetic reprogramming of myeloid cells and adipocytes. Hyperglycemia and high-salt diets can also induce trained immunity in murine models. Recent intervention studies in Tanzania revealed that urban Western-style diets trigger systemic inflammation and immune activation, whereas a traditional plant-based heritage diet limits inflammation. Ex vivo studies suggest that this is caused, at least in part, by modulation of trained immunity. Various individual dietary components, such as the flavone apigenin and the polyphenol resveratrol, are able to prevent trained immunity in vitro. It is exciting to speculate how further molecular elucidation on the modulation of trained immunity by diets or isolated dietary components could help to prevent cardiovascular diseases.

Background: Modeling the human blood-brain barrier (BBB) is limited by the lack of robust protocols to generate induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs). Current methods generate cells that do not fully recapitulate key BMEC functions or the brain endothelial transcriptome identity.

Methods: To address this gap, we combined directed differentiation of human iPSCs into BBB-primed endothelial cells with overexpression of FOXF2 (forkhead box F2) and ZIC3 (zic family zinc finger 3), transcription factors critical for BMEC identity, to generate reprogrammed BMECs (rBMECs) from 3 iPSC lines. We performed immunofluorescence, functional analyses, and bulk RNA sequencing to characterize these cells. We cocultured rBMECs with iPSC-derived astrocytes and pericytes in the MIMETAS microfluidics platform to assess how 3-dimensional culture influences their BBB properties. Finally, we generated rBMECs expressing familial Alzheimer disease mutation APP V717I to elucidate how this genetic variant affects barrier properties compared with exposure to oAβ42 (oligomeric amyloid-β [1-42] peptide).

Results: Transcriptomic and functional analyses show that rBMECs express a subset of the BBB transcriptome and exhibit stronger paracellular barrier properties, lower caveolar-mediated transport, and comparable PGP (P-glycoprotein) activity compared with primary human BMECs. rBMECs interact with human iPSC-derived pericytes and astrocytes to form a 3D neurovascular system in the MIMETAS microfluidics platform with robust BBB properties. Finally, APP V717I rBMECs show decreased barrier integrity and upregulation of inflammatory markers. In contrast, treatment of control rBMECs with oAβ42 increases inflammatory markers, but does not alter barrier integrity.

Conclusions: This protocol generates rBMECs with strong BBB properties and a brain-specific transcriptome signature. In addition, the iPSC-derived 3D neurovascular unit system shows some similar properties to the in vivo human BBB. Finally, familial Alzheimer disease mutation APP V717I alters several BBB-related properties of rBMECs and their inflammatory state, independent of Aβ42 (amyloid-β [1-42] peptide).

Inflammation is a major driver of atherosclerotic cardiovascular disease, and the key roles of trained immunity in initiating and driving this condition are increasingly recognized. However, monitoring trained immunity in patients, particularly inside the atherosclerotic plaque, remains challenging due to a lack of noninvasive readouts. Here, we discuss the potential of nuclear imaging in studying trained immunity in atherosclerotic cardiovascular disease. We show that many trained immunity-relevant radiotracers exist, including ones targeting innate immune cells, metabolic processes, and epigenetic enzymes. However, their use remains limited, and distinguishing trained immunity from other immune processes remains challenging, highlighting the need for more specific trained immunity biomarkers.

Background: People with HIV (PWH) experience higher cardiovascular disease event rates not fully explained by traditional risk factors. Clonal hematopoiesis of indeterminate potential (CHIP), an emerging risk factor for cardiovascular disease in the general population, has been reported to be more prevalent in PWH.

Methods: Using high-coverage targeted CHIP sequencing in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) cardiovascular disease prevention trial, we investigated whether CHIP increases the risk of major adverse cardiovascular events (MACE) among PWH, as well as whether HIV-associated factors were associated with greater CHIP prevalence among PWH. We analyzed whole-exome and targeted sequencing from 4490 PWH without known cardiovascular disease; 1653 (36.8%) were female, and 2039 (45.4%) were Black. MACE was defined by including cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral artery disease, revascularization, or death from an undetermined cause.

Results: A total of 837 (18.6%) had CHIP driver mutations, with 385 (8.6%) at variant allele fraction ≥2% and 61 (1.4%) at variant allele fraction ≥10%. Although overall CHIP was not associated with MACE, the presence of large CHIP (variant allele fraction ≥10%) was associated with increased odds for the first occurrence of myocardial infarction or cardiac catheterization, or revascularization, despite low overall event rates. Adjustments for pitavastatin treatment did not attenuate this association. Furthermore, a larger CHIP clone size was associated with lower CD4 nadir and with increased risk of MACE.

Conclusions: In PWH in the REPRIEVE trial who were low-to-moderate risk for incident cardiovascular disease, CHIP was not associated with increased prospective risk of MACE. However, a large CHIP was associated with increased risk of myocardial infarction and revascularization.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02344290.

Atherosclerosis, a leading cause of cardiovascular diseases, is a chronic, progressive condition driven by lipid dysregulation, endothelial dysfunction, and immune cell infiltration. The PPAR (peroxisome proliferator-activated receptor) family of nuclear receptors (PPARα, PPARδ, and PPARγ) is a pivotal regulator of glucose and lipid metabolism, inflammation, and vascular homeostasis. Emerging evidence reveals that PPARs exert complex, context-dependent effects on atherosclerosis that varies by tissue and cell type. This review summarizes the functions and molecular mechanisms of PPARs in the development and treatment of atherosclerosis, focusing on their roles in lipid metabolism, inflammation, and vascular remodeling. We also evaluate the therapeutic potential of PPAR-targeted strategies and highlight critical knowledge gaps for future research.

The cardiovascular and hematopoietic systems are functionally interconnected through the cardio-hematopoietic axis, a dynamic signaling network that governs hematopoietic responses following cardiac injury. Traditionally viewed primarily as a unidirectional pathway in which cardiac damage mobilizes bone marrow-derived cells to facilitate myocardial repair, emerging evidence now suggests a bidirectional model wherein cardiac-derived cues reciprocally influence hematopoietic stem and progenitor cell fate decisions within the bone marrow niche. This review synthesizes current insights into the mechanistic crosstalk between the injured heart and bone marrow, highlighting the mechanisms by which myocardial injury activates emergency hematopoiesis and immune cell mobilization to support cardiac repair, as well as how cardiac-derived inflammatory and neurohumoral signals remodel the bone marrow niche and reprogram hematopoietic stem cell lineage commitment toward a myeloid-biased, proinflammatory output that amplifies systemic inflammation that contributes to increased cardiovascular risk.

Background: Ischemic stroke requires effective reperfusion therapies to limit brain injury, yet rtPA (recombinant tissue-type plasminogen activator) efficacy is limited, particularly in platelet-rich thrombi. Neutrophil extracellular traps (NETs) and their components, especially histones and DNA, contribute to thrombolysis resistance. Chondroitin sulfate (CS), a glycosaminoglycan with high affinity for extracellular histones, may neutralize their prothrombotic effects and improve outcomes. This study aimed to evaluate the effects of CS in preclinical ischemic stroke models and its impact on components of neutrophil extracellular traps.

Methods: Two mouse models of middle cerebral artery occlusion were used: a fibrin-rich thromboembolic stroke model (rtPA-sensitive) and a platelet-rich aluminum chloride model (rtPA-resistant). Mice received intravenous CS (30-120 mg/kg), rtPA (10 mg/kg), or a combination of both. Lesion volume, tissue recanalization/reperfusion, hemorrhagic transformation, and functional connectivity were assessed via 7T magnetic resonance imaging and ultrafast Doppler imaging. In vitro coagulation-fibrinolysis assays examined the effects of neutrophil extracellular trap components on fibrin polymerization and fibrinolysis, and their modulation by CS±rtPA.

Results: In the fibrin-rich model, CS alone reduced lesion volume by 36% and improved recanalization, comparable to rtPA (43%), without increasing hemorrhagic transformation. CS enhanced functional connectivity recovery at 24 hours, whereas combined CS+rtPA lost these benefits. In the platelet-rich model, CS did not affect lesion size, recanalization, or hemorrhage. In vitro, histones promoted clot stabilization and altered fibrinolysis, effects fully neutralized by equimolar CS in the absence of rtPA. With rtPA, CS's neutralizing capacity was reduced, and histone-driven profibrinolysis was accentuated at higher CS doses. DNA produced opposite effects to histones, and combined DNA+histones masked histone activity, resisting inhibition by CS+DNase.

Conclusions: CS mitigates histone-mediated prothrombotic effects, improves reperfusion and network recovery in fibrin-rich stroke, but loses efficacy in platelet-rich thrombi and when combined with rtPA. These findings support CS as a potential adjunct or alternative therapy, particularly for patients with contraindications to rtPA.