Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

About 10% to 15% of the adult population reports frequent, chronic insomnia symptoms of difficulty initiating or maintaining sleep associated with daytime impairment (ie, insomnia disorder). An additional 30% to 40% report insomnia symptoms at any given time. Not only is insomnia disproportionally more prevalent in individuals with cardiometabolic diseases, but evidence also demonstrates that insomnia, particularly when coupled with objective short sleep duration, increases the risk of developing cardiometabolic diseases. Insomnia is a disorder of 24-hour hyperarousal, a multidimensional construct ranging from cognitive to physiological dysregulation. Physiological hyperarousal in insomnia occurs in the form of hyperactivation of wake-promoting and emotion-regulating areas (eg, glucose metabolism in the ascending reticular activating system), hypothalamic-pituitary-adrenal axis (eg, cortisol levels), sympatho-adrenomedullary axis (eg, norepinephrine levels), cardiac sympathetic-parasympathetic system (eg, heart rate variability), and low-grade inflammation (eg, cytokine levels). Physiological hyperarousal in insomnia inhibits sleep ability, leading to objective short sleep and increasing cardiometabolic disease risk. This brief review summarizes the evidence on the pathophysiologic mechanisms associating insomnia with cardiometabolic disease risk, including current knowledge on the phenotypic heterogeneity of insomnia based on objective sleep duration. Future studies need to test the molecular, cellular, and behavioral mechanisms at play in increasing cardiometabolic disease risk across robustly identified insomnia phenotypes.

Background: Hypertensive disorders of pregnancy (HDP) comprise a spectrum of 4 subtypes: chronic hypertension (cHTN), gestational hypertension (gHTN), preeclampsia, and superimposed preeclampsia (siPE). Although often characterized as a spectrum of disease severity, there have been limited comparative studies of detailed clinical and molecular characteristics of these disorders. We hereby evaluate HDP subtypes using clinical, placental histopathologic, and molecular data to compare similarities and differences between HDP subtypes.

Methods: We used data from an over 10-year-long pregnancy cohort with detailed clinical and placental pathology, as well as placental tissue RNA-sequencing, to compare findings between HDP subtypes using a nested case-control design. Clinical diagnosis was based on current ACOG criteria, and placental gross and histological examination was based on the Amsterdam consensus statement.

Results: Clinical data analysis showed cHTN and gHTN to be more likely to have normal placental pathology, while preeclampsia and siPE were more enriched in maternal vascular malperfusion. RNA-seq showed distinct gene expression signatures and pathway activation across HDP subgroups. We could not identify any molecular evidence that preeclampsia (preeclampsia or siPE) was an advanced stage of hypertensive disorder (gHTN or cHTN), but rather identified distinct gene expression profiles between these entities, suggesting preeclampsia (preeclampsia or siPE) and hypertension (gHTN or cHTN) are distinct pathophysiological conditions. Finally, we found that, in the presence of maternal vascular malperfusion, siPE and preeclampsia share significant gene expression profiles and pathway activation.

Conclusions: Our findings suggest that maternal vascular malperfusion specifically differentiates pregnancies that progress to preeclampsia and siPE. Maternal vascular malperfusion is thought to initiate in early gestation, indicating the cascade to preeclampsia/siPE may be differentiated from gHTN/cHTN early in pregnancy. Incorporating placental histopathologic evaluation is an essential future avenue in probing the cause of HDP.

Background: Atherosclerosis is a leading cause of cardiovascular diseases, and microRNA-26b (miR-26b) has emerged as a significant regulator in its development. This study investigates the role of nonhematopoietic miR-26b in atherosclerosis.

Methods: To study the specific role of nonhematopoietic cell miR-26b in atherosclerosis development, we used a reverse bone marrow transplantation model combined with 12-week Western-type diet feeding.

Results: Nonhematopoietic-specific miR-26b deficiency exacerbated atherosclerosis, characterized by larger plaques with increased collagen and necrotic core content. Enhanced VCAM-1 (vascular cell adhesion molecule 1) expression correlated with elevated leukocyte adhesion in ex vivo perfusion studies. Restoration of miR-26b levels in human coronary artery endothelial cells reduced inflammatory responses and leukocyte adhesion.

Conclusions: Our findings highlight that nonhematopoietic miR-26b plays a protective role in atherosclerosis by modulating endothelial cell function, suggesting potential therapeutic applications for miR-26b mimics in cardiovascular disease management.

Background: Perivascular adipose tissue (PVAT) fine-tunes blood vessel contractility and vascular homeostasis. During obesity and atherosclerosis, PVAT becomes dysfunctional and loses its anticontractile potential. Previously, we reported that global knockout of adipose triglyceride lipase (ATGL), the major enzyme responsible for the breakdown of triglycerides, has the potential to modify PVAT functions. To address the causal relationship between PVAT lipolysis and blood vessel contractility, we analyzed ex vivo vasomotor function of mice with tissue-specific rescue/overexpression or knockout of ATGL in adipose tissue.

Methods: To generate mice lacking ATGL in all tissues except for adipose tissue (ATGL knockout with adipocyte-specific expression of ATGL [A+/AKO]), we crossed adipocyte ATGL-rescued (A+) mice with ATGL-deficient (ATGL knockout [AKO]) mice. Body weight, plasma levels of fatty acids, and blood glucose were compared between A+/AKO and AKO mice. Ex vivo vasoreactivity studies were performed in the absence and presence of PVAT to test for acute and chronic effects of PVAT on vascular function.

Results: Adipocyte-rescued AKO mice (A+/AKO) had significantly less amounts of PVAT than AKO controls while displaying moderate ATGL expression. A+/AKO aortas exhibited decreased anticontractile effects of PVAT compared with AKO aortas. This effect on contractile function was observed in an agonist-specific manner without affecting smooth muscle cell function or endothelium-dependent relaxation. Assessment of cardiac function using the Langendorff setup revealed that adipocyte ATGL selectively modulated vascular contractility without affecting systolic or diastolic performance. Studies using mice that express ATGL solely in cardiac muscle and adipocyte-specific ATGL knockout mice verified our findings in A+/AKO mice, revealing acute and chronic effects of adipocyte lipolysis on vasoreactivity.

Conclusions: We provide the first evidence that changes in adipocyte lipolysis have the potential to regulate blood vessel contractility. Ablation of ATGL in adipocytes decreases vascular contractility and, thus, has the potential to prevent PVAT dysfunction in obesity and atherosclerosis.

Background: Abdominal aortic aneurysm (AAA), a pathological dilation of the abdominal aorta, is primarily driven by chronic aortic wall inflammation. The well-established anti-inflammatory microRNA 146a (miR-146a) has been implicated as a key regulator in various chronic inflammatory pathologies. However, its potential functional role in the pathogenesis of AAA remains to be elucidated.

Methods: We constructed Ang II (angiotensin II)-induced and PPE (porcine pancreatic elastase)-induced models in global miR-146a knockout mice, vascular smooth muscle cell (VSMC)-specific miR-146a knockout mice, and macrophage-specific miR-146a knockout mice, respectively, to explore the role of miR-146a in AAA. Western blot, quantitative polymerase chain reaction, and immunohistochemistry were used to detect the levels of aortic proinflammatory markers and VSMC contractile proteins, whereas flow cytometry was used to assess M1/M2-like macrophage polarization. To validate the downstream mechanism, dibenzazepine was intraperitoneally injected to inhibit the Notch1 pathway in rescue experiments.

Results: In the Ang II-induced and PPE-induced model, global knockout of miR-146a promoted AAA development, increased maximal aortic diameter, exacerbated medial elastin degradation, and upregulated aortic proinflammatory markers (COX2 [cyclooxygenase 2], MMP [matrix metalloproteinase] 2, MMP9, and CCL2 [chemokine (C-C motif) ligand 2]). Flow cytometry analysis revealed that global miR-146a deficiency also induced macrophage polarization toward the inflammatory M1 phenotype. Conditional deletion of miR-146a in VSMCs and macrophages largely replicated AAA formation and proinflammatory effects. Furthermore, AAV9 (adeno-associated virus)-mediated miR-146a knockdown significantly reduced VSMC contractile proteins CNN1 (calponin 1), SM22α (smooth muscle 22α), and α-SMA (α-smooth muscle actin) in mouse aortas at 7 days post-Ang II perfusion. Mechanistically, Notch1 antagonist dibenzazepine effectively rescued AAA characteristics and M1 biomarkers while enhancing M2 biomarkers in global miR-146a knockout mice.

Conclusions: The absence of miR-146a potentiates AAA formation by promoting VSMC phenotypic switching, Notch1 signaling-mediated aortic inflammation, and macrophage M1 polarization. Thus, miR-146a plays a critical role in maintaining aortic structural integrity to prevent aneurysmal pathogenesis.

Background: The alternative pathway (AP) plays a crucial role in triggering complement activation and promoting chronic inflammation. This study aims to investigate the longitudinal association between AP and atherosclerosis, and explore the potential role of gut microbiota and inflammatory factors in their association.

Method: This study was based on a 9-year prospective cohort of 3382 participants from Guangzhou, China (mean age±SD, 57.75±5.85 years; 68.8% female), with data on serum APACPs (AP-associated complement proteins) and carotid plaque (measured by ultrasound) repeatedly measured up to 3×. Baseline inflammatory markers were evaluated in 923 participants, and gut shotgun metagenome data were obtained from 1567 participants. Mendelian randomization analysis was performed using genome-wide significant genetic variants as instrumental variables to suggest potential causal associations.

Results: Both longitudinal and prospective analyses consistently demonstrated positive associations between carotid plaque and 3 complement components: C3 (complement C3; odds ratios [95% Cl] for the highest versus lowest quartiles, 1.36 [1.07-1.74] in longitudinal analysis and 1.29 [1.06-1.56] in prospective analysis), CFB (complement factor B; 1.36 [1.07-1.72] in longitudinal analysis and 1.39 [1.15-1.69] in prospective analysis), and CFH (complement factor H; 1.39 [1.10-1.76] in longitudinal analysis and 1.31 [1.07-1.61] in prospective analysis). Mendelian randomization analysis suggested a potential causal association between CFB and carotid plaque. Inflammatory factors (CRP [C-reactive protein] and IL-6 [interleukin-6]) and microbial species (Ruminococcus bromii, Roseburia hominis, Rothia mucilaginosa, Collinsella stercoris, Olsenella scatoligenes, and Bacteroides massiliensis) were significantly associated with both APACPs and carotid plaque (P<0.05). For example, butyrate-producing bacterium R bromii was inversely associated with CFB and carotid plaque (odds ratios [95% CI], 0.83 [0.79-0.88]) and may mediate the CFB-carotid plaque association (proportion mediated, 13.5%; P=0.005). Microbial risk score (weighted sum of selected microbial species; proportion mediated, 42.6%; P<0.001) and total immune factors (the sum of all inflammatory factors; proportion mediated, 19.0%; P=0.002) mediated the association between Total-APACPs (sum of standardized carotid plaque-related APACPs [C3, CFB, and CFH]) and carotid plaque.

Conclusions: Our study showed a negative association between the AP and carotid plaque in a longitudinal cohort. Gut microbiota and inflammatory biomarkers may provide mechanistic insights into the association between the AP and atherosclerosis. Our findings pave the way for the development of new therapeutic targets for atherosclerosis.

Background: We aimed to compare the molecular and clinical characteristics of patients identified in Italy as affected by either familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) and to assess the overall benefit of novel triglyceride-lowering therapies prescribed to these patients within the routine clinical care.

Methods: From the national LIPIGEN-sHTG (Lipid Transport Disorders Italian Genetic Network-Severe Hypertriglyceridemia) registry, 169 patients (57 FCS, 51 MCS, 61 variant-negative, variant-negative MCS) were retrospectively analyzed. Data on clinical and genetic characteristics, medical history, and medications were collected. Peak triglyceride levels were used to define untreated lipid phenotypes.

Results: In FCS, 72% exhibited biallelic LPL and 28% non-LPL variants; in MCS, 38% (n=19) carried LPL variants, and 38% (n=19) carried APOA5 variants, whereas the remaining individuals were carriers of LMF1 (n=3), GPIHBP1 (n=2), and CREB3L3 or GPD1 variants (n=8), respectively. Peak TGs were highest in FCS (3000 mg/dL [interquartile range, 2116.0-4265.0]), followed by MCS (1817 mg/dL [interquartile range, 1370.0-3062.0]) and variant-negative MCS (1340.0 mg/dL [interquartile range, 946.5-2508.5]; P<0.001). FCS showed a 3.4-fold higher risk of acute pancreatitis than others, whereas no significant differences were observed between groups in the prevalence of atherosclerotic cardiovascular diseases. In the subset of patients with FCS receiving novel therapies (lomitapide or volanesorsen; 35%), triglyceride levels decreased by 62%, as compared with an 11% reduction in those on conventional treatment. Across the cohort, posttreatment triglyceride levels were 895 mg/dL in FCS, 352 mg/dL in MCS, and 386 mg/dL in variant-negative MCS.

Conclusions: As compared with MCS, patients with FCS showed a more severe phenotype and higher prevalence of LPL variants. Lomitapide and volanesorsen provide better triglyceride control, yet only one-third of FCS were treated with these drugs in the routine clinical practice.

Background: Movement of circulating lipids into tissues and arteries requires transfer across the endothelial cell (EC) barrier. This process allows the heart to obtain fatty acids, its chief source of energy, and apoB-containing lipoproteins to cross the arterial endothelial barrier, leading to cholesterol accumulation in the subendothelial space. Multiple studies have established elevated postprandial TRLs (triglyceride-rich lipoproteins) as an independent risk factor for cardiovascular disease. We explored how chylomicrons affect ECs and transfer their fatty acids across the EC barrier.

Methods: We had reported that media from chylomicron-treated ECs lead to lipid droplet formation in macrophages. To determine the responsible component of this media, we assessed whether removing the extracellular vesicles (EVs) would obviate this effect. EVs from control and treated cells were then characterized by protein, lipid, and microRNA content. We also studied the EV-induced transcription changes in macrophages and ECs and whether knockdown of SR-BI (scavenger receptor-BI) altered these responses. In addition, using chylomicrons labeled with [¹³C]oleate, we studied the uptake and release of this labeled by ECs.

Results: Chylomicron treatment of ECs led to an inflammatory response that included production of EVs that drove macrophage lipid droplet accumulation. The EVs contained little free fatty acids and triglycerides, but abundant phospholipids and diacylglycerols. In concert with this, [¹³]C labeled chylomicron triglycerides exited ECs primarily in phospholipids. EVs from chylomicron-treated versus untreated ECs were larger, more abundant, and contained specific microRNAs. Treatment of macrophages and naive ECs with media from chylomicron-treated ECs increased expression of inflammatory genes.

Conclusions: EC chylomicron metabolism produces EVs that increase macrophage inflammation and create LDs. Media containing these EVs also increases EC inflammation, illustrating an autocrine inflammatory process. Fatty acids within chylomicron triglycerides are converted to phospholipids within EVs. Thus, EC uptake of chylomicrons constitutes an important pathway for vascular inflammation and tissue lipid acquisition.

Background: Inflammation potentiates aortic valve calcification (AVC). ⁶⁸Ga-DOTATATE (gallium-68 DOTA-(Tyr³)-octreotate), a positron emission tomography tracer that binds to somatostatin receptors, provides a measure of tissue inflammation. However, the diagnostic and prognostic values of aortic valve (AV) ⁶⁸Ga-DOTATATE uptake in AVC remain unexplored. Here, we tested whether AV ⁶⁸Ga-DOTATATE uptake predicts the progression of AVC.

Methods: A total of 683 individuals (median age, 63 years; 46% male) underwent clinical ⁶⁸Ga-DOTATATE positron emission tomography/computed tomography imaging from 2017 to 2023; 209 had follow-up imaging (median, 1.3 years interval). AV inflammation was measured as the maximum standardized uptake value of ⁶⁸Ga-DOTATATE uptake within the AV on baseline positron emission tomography/computed tomography. AVC was quantified on baseline and follow-up computed tomography scans (Hounsfield units >130). AVC progression was assessed as the difference between baseline and follow-up AVC. Individuals with a square root difference of annualized AVC change ≥2.5 were characterized as progressors and <2.5 as nonprogressors. Demographic and clinical data were collected from medical records.

Results: Baseline AV ⁶⁸Ga-DOTATATE uptake correlated with baseline AVC (standardized ρ=0.12; P=0.002). Furthermore, baseline AV ⁶⁸Ga-DOTATATE uptake associated with AVC progression (odds ratio [OR], 3.0 [95% CI, 1.4-6.4]; P=0.004) and remained significant after separately adjusting for baseline AVC (OR, 3.1 [95% CI, 1.5-6.6]), sex (OR, 4.0 [95% CI, 1.7-9.0]), hypertension (OR, 2.8 [95% CI, 1.3-6.2]), diabetes (OR, 3.0 [95% CI, 1.4-6.4]), hyperlipidemia (OR, 2.4 [95% CI, 1.1-5.3]), smoking (OR, 3.1 [95% CI, 1.5-6.7]), chronic kidney disease (OR, 2.9 [95% CI, 1.4-6.3]), and body mass index (OR, 3.0 [95% CI, 1.4-6.3]), became insignificant when adjusting to age (OR, 1.9 [95% CI, 0.8-4.3]).

Conclusions: Our study highlights the use of ⁶⁸Ga-DOTATATE for assessing AV inflammation and predicting AVC progression. These findings underscore the role of inflammation in AVC progression and have potential implications for risk assessment and evaluating therapies in AV disease.

Background: Pericytes are vascular mural cells, critical to the formation and maintenance of tightly regulated microvascular networks, including the inner blood-retinal barrier, and their dysfunction is characteristic of many vascular diseases, including diabetic retinopathy. Although donor eye and animal studies have suggested a link between pericyte loss and retinal vascular leakage, this relationship has not been explored in living humans, nor has the role of pericytes in predicting other complications, like albuminuria, in diabetes.

Methods: In this pilot study, we utilized adaptive optics scanning laser ophthalmoscopy to image and quantify retinal capillary pericytes in humans with diabetes. Leakage was manually delineated on fluorescein angiography to calculate macular leakage (%), whereas optical coherence tomography and optical coherence tomography-angiography evaluated retinal thickness and capillary nonperfusion, respectively. In addition, urine albumin/creatinine ratios (mg/g) were extracted from charts, post hoc, to evaluate the relationship between retinal pericytes and albuminuria in a subpopulation (n=14).

Results: The study included 24 eyes from 23 patients with a range of diabetic retinopathy severity spanning from no diabetic retinopathy to proliferative diabetic retinopathy. Notably, capillary pericyte density showed a strong, negative correlation to macular leakage (r=-0.68; P<0.001) and moderate correlation to optical coherence tomography thickness (r=-0.45; P=0.027). Receiver operating characteristics analysis identified pericyte density thresholds (≤13.2 and 13.4 pericytes per 100 µm) that showed high area under the curves for detecting macular leakage (area under the curve, 0.87) and volumetric thickness (area under the curve, 0.80). Interestingly, albumin/creatinine ratios were significantly higher in individuals with ≤13.2 retinal capillary pericyte per 100 µm compared with those above the threshold (n=14, P=0.046).

Conclusions: Retinal capillary pericyte density, quantified in vivo, correlates significantly with macular thickening and angiographic leakage. We identified a threshold of pericyte loss that distinguishes individuals based on macular leakage status and albuminuria, providing important insights into retinal pericytes and their potential utility as a biomarker of vascular permeability.