Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

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: The venous and lymphatic outflows from organs may contain molecular signatures related to tissue function, but deep biomolecular analyses that compare outflow composition are lacking. Here, using blood and lymph samples from a piglet model system and mass spectrometry analysis, we compare protein and lipid cargo from 9 venous and 3 lymph depots centered on intestinal outflow.

Methods: We obtained venous blood and plasma from piglets using new methods for dissection and sample collection. We applied mass spectrometry-based proteomics and lipidomics, using both a low-volume method and an additional proteomics sample preparation method, the Seer Proteograph XT high coverage method for the proteomics.

Results: We detected 622 proteins and 1315 lipids across lymph and plasma. With the additional Seer proteomics method, we detected a further 7771 proteins across a subset of samples. We observed both expected and novel enrichments of proteins, including CCL21 and IGFBP (insulin-like growth factor-binding protein) 7 as proteins strongly enriched in lymph. When comparing lymph depots, we found that thoracic duct lymph is distinct from lymph draining the proximal and distal small intestine, especially in their lipidomic profiles, reflecting differences in dietary lipid uptake. By performing integrative multiomics of proteomics and lipidomics, we show that apos (apolipoproteins), such as the related apoA1 and apoA2 proteins, correlate with different lipid profiles and may associate with distinct functions across the plasma depots.

Conclusions: These data identify molecules and biomarkers selectively enriched in adjacent lymph and venous drainage depots from the gastrointestinal tract. The analyses and figures present in this work are expanded upon in an interactive companion Web application at gutveinlymphomics.com, facilitating access to our integrated multiomics and advancing understanding of biomolecular trends across the intestinal tract.

Despite major advances in acute reperfusion therapies, patients surviving ischemic stroke or myocardial infarction remain at high risk for long-term cardiovascular and metabolic comorbidities. Emerging evidence identifies trained immunity, the long-lasting reprogramming of innate immune progenitors, as a central driver of this interorgan communication. Sterile insults such as stroke or myocardial infarction imprint persistent inflammatory memory via long-lasting reprogramming of bone marrow hematopoietic progenitors, biasing myelopoiesis and generating proinflammatory monocytes that target distant organs. This central trained immunity explains how a single ischemic event can precipitate cardiac dysfunction, accelerate atherosclerosis, or exacerbate metabolic disease, thereby contributing to multimorbidity in vascular patients. Understanding these systemic immune circuits provides a conceptual framework for developing interventions that interrupt maladaptive inflammatory memory. Finally, we discuss emerging therapeutic strategies to prevent maladaptive innate immune memory and mitigate chronic vascular inflammation and multimorbidity.

Background: Obesity predisposes individuals to multiple pathologies, including metabolic dysfunction-associated steatotic liver disease and diabetes. Although it is known that accumulation of proinflammatory macrophages within adipose tissues drives adiposity and provokes obesity-linked sequelae, the molecular mechanisms that provoke macrophage dysfunction in obesity remain elusive. Macrophages express high levels of uPA (urokinase plasminogen activator), and uPA has been implicated in leukocyte migration.

Methods: Human adipose tissues from patients receiving bariatric surgery were collected and analyzed for uPA protein levels. To determine the impact of uPA in adipose tissue and subsequent high-fat diet (HFD)-induced weight gain and metabolic diseases, a novel mouse model with a conditional knockout of uPA (Plau^fl/fl) was generated. Plau^WT/WT, Plau^KO/KO (global uPA deficiency), and Plau^fl/fl/LysM Cre+ (conditional uPA deficiency in macrophages) mice were fed low-fat diet or HFD for up to 20 weeks.

Results: Protein levels of visceral adipose tissue uPA positively correlated with body mass index in patients with obesity, and uPA levels decreased in adipose tissue 2 years after bariatric surgery. The expression and activity of uPA also increased in the adipose tissue of HFD-fed control mice. Plau^KO/KO mice displayed reduced weight gain and metabolic sequelae through 14 weeks on a HFD compared with Plau^WT/WT mice, but not with prolonged HFD feeding. Interestingly, Plau^fl/fl/LysM Cre+ mice developed HFD-induced metabolic pathologies equivalently to Plau^WT/WT mice.

Conclusions: Our findings suggest that global uPA deletion, but not selective deletion of uPA in LysM+ myeloid cells, attenuates the development of early-stage HFD-driven obesity and pathologies consistent with metabolic syndrome.

Perivascular adipose tissue (PVAT) has been widely studied over the past 2 decades for its anticontractile function, morphology, and adipokine secretion. However, most data were obtained from males, with few studies on female PVAT. Indeed, the PVAT secretome, adipocyte phenotype, progenitor cells, and responses to cardiovascular risk factors exhibit sex differences and may be modulated by sex hormones. Here, we compiled data evaluating PVAT based on sex differences or focused on the female sex. Sex comparisons in PVAT function and morphology under physiological conditions and in pathological states such as dyslipidemia, atherosclerosis, obesity, heart failure, and hypertension have been briefly reviewed.

Background: Pulmonary hypertension (PH) due to left heart disease (group 2 PH) is associated with a worse prognosis than isolated heart failure. Both pulmonary arterial hypertension (group 1 PH) and group 2 PH are involved in pulmonary artery (PA) remodeling, which is potentially driven by shared molecular mechanisms. The aim of this study was to investigate the underlying processes contributing to PA remodeling in group 2 PH.

Methods: To mimic the response to a left-sided pressure load, pulmonary arterial smooth muscle cells (PASMCs) were subjected to mechanical stretch. RNA sequencing of PAs from patients with group 2 PH was performed using the Gene Expression Omnibus database. Mice with transverse aortic constriction and spontaneously hypertensive rats were used as group 2 PH models, and they were treated with adeno-associated virus via intratracheal instillation.

Results: RNA sequencing of PASMCs after the stretch stress identified 1585 genes specifically upregulated in PASMCs from patients with group 1 PH. Further PA and plasma analyses from patients with group 2 PH, integrated with group 1 PH findings, identified enhancement of TGF-β (transforming growth factor-beta) signaling by the INHBA (inhibin subunit beta A) as a key feature. Metabolomics revealed that stretch-induced mitochondrial dysfunction in PASMCs caused lactic acidosis via enhancement of PDK1 (pyruvate dehydrogenase kinase 1) and c-MYC, leading to increased INHBA expression. Mice with transverse aortic constriction exhibited increased INHBA expression, decreased PDH (pyruvate dehydrogenase) expression, and acidic alterations in PAs. Targeted silencing of INHBA or PDK1 using adeno-associated virus in mice with transverse aortic constriction attenuated PA remodeling, improved right ventricular function, and reduced PH.

Conclusions: Integrated RNA sequencing and metabolomics with stretched PASMCs and animal models identified mitochondrial dysfunction and subsequent acidic alterations as stimulators of increased INHBA expression and TGF-β signaling. These mechanisms contributed to PA remodeling in group 2 PH and provided potential therapeutic strategies.

Sleep behavior has emerged as an important determinant of cardiometabolic health. However, to date, much attention has focused on sleep duration with accumulating evidence resulting in leading medical organizations to include adequate sleep duration in their recommendations for disease risk prevention and health promotion. However, sleep is a multidimensional construct that extends beyond sleep duration and includes factors related to the variability of duration but also to the regularity in its timing across days. These concepts, termed sleep duration variability (day-to-day differences in sleep amounts) and sleep timing regularity (day-to-day differences in sleep timing), can influence the circadian system and have independent health effects beyond sleep duration per se. Here, we assess the literature evaluating the association of fluctuations in sleep behaviors over time and cardiometabolic risk factors and their potential implications for chronic disease development. We conclude that large-scale population-based studies support an adverse relation between fluctuations in sleep behaviors and cardiovascular disease risk markers, but caution that causality should be evaluated in clinical intervention studies.

Peripheral artery disease commonly refers to diffuse atherothrombotic disease of the arteries supplying the legs. Peripheral artery disease has been relatively understudied and has not been subject to the same intensive scrutiny and research that characterizes coronary artery disease. Moreover, the diagnosis of peripheral artery disease can be complicated by the presence of arterial calcification. Here, we provide a brief report on the current understanding of peripheral vascular calcification to include the following sections: basic mechanisms, anatomic distribution of arterial calcification, manifestations, risk factors, measurement of peripheral calcification, nonsurgical treatments, and surgical interventions.

Perivascular adipose tissue (PVAT) is a metabolically active tissue that influences vascular function through paracrine signaling of adipokines. Pathologically altered PVAT is associated with proinflammatory, pro-oxidative, and proatherogenic signaling in coronary vessels, and consequently contributes to the pathophysiological mechanisms underlying atherosclerosis. Bidirectional cross talk from inflamed vasculature can also induce phenotypic changes in the PVAT that can be detected noninvasively with cross-sectional imaging. Imaging modalities like computed tomography are readily available in clinical settings, and PVAT characterization with Fat Attenuation Index has emerged as a valuable prognostic tool that quantifies coronary inflammation. This article reviews the imaging, quantification, and novel radiotranscriptomic analysis of PVAT. We also describe how these could integrate into artificial intelligence-enabled risk-prediction models for personalizing medical therapy guided by an individual's inflammatory risk, and how this approach already changes clinical management in healthcare systems where it has been adopted.