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Cardiovascular disease (CVD) is a leading cause of death in chronic kidney disease (CKD). Hemodialysis is one of the main treatments for patients with end-stage kidney disease. Epidemiological data has shown that acute myocardial infarction (AMI) accounts for the main reason for death in patients with CKD under hemodialysis therapy. Immune dysfunction and changes in metabolism (including a high level of inflammatory cytokines, a disorder of lipid and mineral ion homeostasis, accumulation of uremic toxins et al.) during CKD can deteriorate stability of atherosclerotic plaque and promote vascular calcification, which are exactly the pathophysiological mechanisms underlying the occurrence of AMI. Meanwhile, the hemodialysis itself also has adverse effects on lipoprotein, the immune system and hemodynamics, which contribute to the high incidence of AMI in these patients. This review aims to summarize the mechanisms and further promising methods of prevention and treatment of AMI in CKD patients undergoing hemodialysis, which can provide an excellent paradigm for exploring the crosstalk between the kidney and cardiovascular system.
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Infarto do Miocárdio , Diálise Renal , Insuficiência Renal Crônica , Humanos , Diálise Renal/efeitos adversos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/terapia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , AnimaisRESUMO
Metabolic diseases are a group of disorders caused by metabolic abnormalities, including obesity, diabetes, non-alcoholic fatty liver disease, and more. Increasing research indicates that, beyond inherent metabolic irregularities, the onset and progression of metabolic diseases are closely linked to alterations in the gut microbiota, particularly gut bacteria. Additionally, fecal microbiota transplantation (FMT) has demonstrated effectiveness in clinically treating metabolic diseases, notably diabetes. Recent attention has also focused on the role of gut viruses in disease onset. This review first introduces the characteristics and influencing factors of gut viruses, then summarizes their potential mechanisms in disease development, highlighting their impact on gut bacteria and regulation of host immunity. We also compare FMT, fecal filtrate transplantation (FFT), washed microbiota transplantation (WMT), and fecal virome transplantation (FVT). Finally, we review the current understanding of gut viruses in metabolic diseases and the application of FVT in treating these conditions. In conclusion, FVT may provide a novel and promising treatment approach for metabolic diseases, warranting further validation through basic and clinical research.
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Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Doenças Metabólicas , Viroma , Humanos , Transplante de Microbiota Fecal/métodos , Doenças Metabólicas/terapia , Animais , Fezes/virologia , Fezes/microbiologiaRESUMO
BACKGROUND AND PURPOSE: Currently little is known about the joint association of lipoprotein (a) [Lp(a)] and Lipoprotein-associated phospholipase A2 (Lp-PLA2) with stroke recurrence. METHODS: In this prospective multicenter cohort study, 10,675 consecutive acute ischemic stroke (IS) and transient ischemic attack patients (TIA) with Lp(a) and Lp-PLA2 were enrolled. The association of stroke recurrence within 1 year with Lp(a) and Lp-PLA2 was assessed using Cox proportional hazards models and Kaplan-Meier curves. The interaction between Lp(a) and Lp-PLA2 with stroke recurrence was evaluated by multiplicative and additive scales. RESULTS: A significant joint association of Lp(a) and Lp-PLA2 with the risk of stroke recurrence was observed. Multivariate cox regression analysis demonstrated that the combination of elevated Lp(a) (≥ 50 mg/dL) and Lp-PLA2 (≥175.1 ng/ml) was independently associated with the risk of stroke recurrence (adjusted hazard ratio: 1.42; 95 % CI: 1.15-1.76). Both significant multiplicative [(exp(ß3):1.63, 95 % CI: 1.17-2.29, P = 0.004] and additive interaction (RERI:0.55, 95 % CI: 0.20-0.90, P = 0.002; AP: 0.39, 95 %CI, 0.24-0.53) were observed between Lp(a) and Lp-PLA2. CONCLUSIONS: Our results indicated that Lp(a) and Lp-PLA2 have a joint association with the risk of stroke recurrence in IS/TIA patients. Patients with concomitant presence of elevated Lp(a) and Lp-PLA2 have greater risk of stroke recurrence.
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The gut microbiota is a complex community of microorganisms inhabiting the intestinal tract, which plays a vital role in human health. It is intricately involved in the metabolism, and it also affects diverse physiological processes. The gut-lung axis is a bidirectional pathway between the gastrointestinal tract and the lungs. Recent research has shown that the gut microbiome plays a crucial role in immune response regulation in the lungs and the development of lung diseases. In this review, we present the interrelated factors concerning gut microbiota and the associated metabolites in pulmonary hypertension (PH), a lethal disease characterized by elevated pulmonary vascular pressure and resistance. Our research team explored the role of gut-microbiota-derived metabolites in cardiovascular diseases and established the correlation between metabolites such as putrescine, succinate, trimethylamine N-oxide (TMAO), and N, N, N-trimethyl-5-aminovaleric acid with the diseases. Furthermore, we found that specific metabolites, such as TMAO and betaine, have significant clinical value in PH, suggesting their potential as biomarkers in disease management. In detailing the interplay between the gut microbiota, their metabolites, and PH, we underscored the potential therapeutic approaches modulating this microbiota. Ultimately, we endeavor to alleviate the substantial socioeconomic burden associated with this disease. This review presents a unique exploratory analysis of the link between gut microbiota and PH, intending to propel further investigations in the gut-lung axis.
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Combined hyperlipidemia (CHL) manifests as elevated cholesterol and triglycerides, associated with fatty liver and cardiovascular diseases. Emerging evidence underscores the crucial role of the intestinal microbiota in metabolic disorders. However, the potential therapeutic viability of remodeling the intestinal microbiota in CHL remains uncertain. In this study, CHL was induced in low-density lipoprotein receptor-deficient (LDLR-/-) hamsters through an 8-week high-fat and high-cholesterol (HFHC) diet or a 4-month high-cholesterol (HC) diet. Placebo or antibiotics were administered through separate or cohousing approaches. Analysis through 16S rDNA sequencing revealed that intermittent antibiotic treatment and the cohousing approach effectively modulated the gut microbiota community without impacting its overall abundance in LDLR-/- hamsters exhibiting severe CHL. Antibiotic treatment mitigated HFHC diet-induced obesity, hyperglycemia, and hyperlipidemia, enhancing thermogenesis and alleviating nonalcoholic steatohepatitis (NASH), concurrently reducing atherosclerotic lesions in LDLR-/- hamsters. Metabolomic analysis revealed a favorable liver lipid metabolism profile. Increased levels of microbiota-derived metabolites, notably butyrate and glycylglycine, also ameliorated NASH and atherosclerosis in HFHC diet-fed LDLR-/- hamsters. Notably, antibiotics, butyrate, and glycylglycine treatment exhibited protective effects in LDLR-/- hamsters on an HC diet, aligning with outcomes observed in the HFHC diet scenario. Our findings highlight the efficacy of remodeling gut microbiota through antibiotic treatment and cohousing in improving obesity, NASH, and atherosclerosis associated with refractory CHL. Increased levels of beneficial microbiota-derived metabolites suggest a potential avenue for microbiome-mediated therapies in addressing CHL-associated diseases.
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Evidence of the precise biological pathway responsible for acute cardiovascular events triggered by particulate matter (PM) exposure from anthropogenic emissions is sparse. We investigated the associations of biomarkers relevant to the pathophysiology of atherothrombosis (ceramide metabolism, pro-inflammatory response, and blood coagulation) with primary and secondary components in particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5). A total of 152 healthy participants were followed with four repeated clinical visits between September 2019 and January 2020 in Beijing. Exposure to ambient inorganic aerosols (sulfate, nitrate, ammonium, and chloride), as well as organic aerosols (OA) in PM2.5, was measured by a real-time aerosol chemical speciation monitor, and sources of OA were performed by positive matrix factorization. We found significant increases of 101.9-397.9% in ceramide indicators associated with interquartile-range increases in inorganic aerosols and OA prior to 72 h of exposure. Higher levels of organic and inorganic aerosols in PM2.5 were associated with increases of 3.1-6.0% in normal T cells regulated upon activation and expressed and secreted relevant to the pro-inflammatory response; increases of 276.9-541.5% were observed in D-dimers relevant to coagulation. Detrimental effects were further observed following OA exposure from fossil fuel combustion. Mediation analyses indicated that ceramide metabolism could mediate the associations of PM2.5 components with pro-inflammatory responses. Our findings expand upon the current understanding of potential pathophysiological pathways of cardiovascular events posed by ambient particulates and highlight the importance of reducing primary and secondary PM from anthropogenic combustions.
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Introduction The angiotensin-converting enzyme-2 (ACE-2) and its shedding product [soluble ACE-2 (sACE-2)] are implicated in adverse cardiovascular outcomes. However, the relationship between sACE-2 and stroke recurrence is unknown. Herein, we examined the relationship of sACE-2 with stroke recurrence in patients with ischemic stroke or transient ischemic attack (TIA). Methods Data were obtained from the Third China National Stroke Registry (CNSR-â ¢). Eligible cases consisted of 494 patients who developed recurrent stroke within 1-year follow-up, 494 controls were selected using age- and sex- matched with a 1:1 case-control ratio. Conditional logistic regressions were used to evaluate the association between sACE-2 and recurrent stroke. The main outcomes were recurrent stroke within 1 year. Results Among 988 patients included in this study, the median (interquartile range) of sACE-2 was 25.17 (12.29-45.56) ng/mL. After adjustment for conventional confounding factors, the odds ratio with 95% confidence interval in the highest quartile versus the lowest quartile was 1.68 (1.12-2.53) for recurrent stroke within 1-year follow-up. Subgroup analysis showed that the association between elevated plasma level of sACE-2 and stroke recurrence was significant in patients with higher systemic inflammation, as indicated by high sensitivity C reactive protein (hsCRP) ≥ 2 mg/L (adjusted OR: 2.33 [95% CI, 1.15-4.72]) and neutrophil (NEUT) counts ≥ median (adjusted OR: 2.66 [95% CI, 1.35-5.23]), but not significant in patients with lower systemic inflammation. Discussion Elevated plasma sACE-2 concentration was associated with increased risk of recurrent stroke.
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BACKGROUND: Gut microbiota assumes an essential role in the development and progression of pulmonary arterial hypertension (PAH). Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite, is correlated with the prognosis of patients with PAH. However, the correlation between changes in TMAO (ΔTMAO) and the prognosis of PAH remains elusive. OBJECTIVES: To investigate the association between ΔTMAO and prognosis of PAH, and explore whether dynamic assessment of TMAO level was superior to measurement at a single time point in predicting prognosis. DESIGN: Single-center cohort study. METHODS: Consecutive patients diagnosed with PAH and had at least two TMAO measurements taken from May 2019 to June 2020 were eligible. The outcome events of this study were defined as adverse clinical events. RESULTS: A total of 117 patients with PAH who had two TMAO measurements and follow-up were included in this study. Patients with ΔTMAO ⩾1.082 µmol/L had over four times increased risk of adverse clinical events than their counterparts after adjusting for confounders [hazard ratio (HR) 4.050, 95% confidence interval (CI): 1.468-11.174; p = 0.007]. Patients with constant high TMAO levels at both time points had the highest risk of adverse clinical events compared with patients with constant low TMAO levels (HR 3.717, 95% CI: 1.627-8.492; p = 0.002). ΔTMAO was also associated with changes in parameters reflecting PAH severity (p < 0.05). CONCLUSION: Changes in TMAO were independently correlated with prognosis in patients with PAH, irrespective of baseline level of TMAO. ΔTMAO also correlated with alteration in disease severity. Repeated assessment of TMAO level contributes to better identification of patients with increased risk of adverse clinical events.
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Microbioma Gastrointestinal , Hipertensão Arterial Pulmonar , Humanos , Hipertensão Arterial Pulmonar/diagnóstico , Estudos de Coortes , MetilaminasRESUMO
Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5+ (Cdh5+) cerebral vascular cells in naturally aging mice and confirmed it in human brain samples. Global or Cdh5+ cell-specific CX43 deletion in mice exacerbated BBB dysfunction during aging. The CX43-dependent effect was not due to its canonical gap junction function but was associated with reduced NAD+ levels and mitochondrial dysfunction through NAD+-dependent sirtuin 3 (SIRT3). CX43 interacts with and negatively regulates poly(ADP-ribose) polymerase 1 (PARP1). Pharmacologic inhibition of PARP1 by olaparib or nicotinamide mononucleotide (NMN) supplementation rescued NAD+ levels and alleviated aging-associated BBB leakage. These findings establish the endothelial CX43-PARP1-NAD+ pathway's role in vascular aging and identify a potential therapeutic strategy to combat aging-associated BBB leakage with neuroprotective implications.
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Conexina 43 , NAD , Animais , Humanos , Camundongos , Envelhecimento/fisiologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , NAD/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismoRESUMO
Air pollution has been associated with the development of atherosclerosis; however, the pathophysiological mechanisms underlying pro-atherosclerotic effects of air pollution exposure remain unclear. We conducted a prospective panel study in Beijing and recruited 152 participants with four monthly visits from September 2019 to January 2020. Linear mixed-effect models were applied to estimate the associations linking short-term air pollution exposure to biomarkers relevant to ceramide metabolism, pro-inflammation (neutrophil extracellular traps formation and systemic inflammation) and pro-atherosclerotic responses (endothelial stimulation, plaque instability, coagulation activation, and elevated blood pressure). We further explored whether ceramides and inflammatory indicators could mediate the alterations in the profiles of pro-atherosclerotic responses. We found that significant increases in levels of circulating ceramides of 9.7% (95% CIs: 0.7, 19.5) to 96.9% (95% CIs: 23.1, 214.9) were associated with interquartile range increases in moving averages of ambient air pollutant metrics, including fine particulate matter (PM2.5), black carbon, particles in size fractions of 100-560 nm, nitrogen dioxide, carbon monoxide and sulfur dioxide at prior up to 7 days. Higher air pollution levels were also associated with activated neutrophils (increases in citrullinated histone H3, neutrophil elastase, double-stranded DNA, and myeloperoxidase) and exacerbation of pro-atherosclerotic responses (e.g., increases in vascular endothelial growth factor, lipoprotein-associated phospholipase A2, matrix metalloproteinase-8, P-selectin, and blood pressure). Mediation analyses further showed that dysregulated ceramide metabolism and potentiated inflammation could mediate PM2.5-associated pro-atherosclerotic responses. Our findings extend the understanding on potential mechanisms of air pollution-associated atherosclerosis, and suggest the significance of reducing air pollution as priority in urban environments.
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Poluentes Atmosféricos , Poluição do Ar , Aterosclerose , Armadilhas Extracelulares , Humanos , Ceramidas/análise , Esfingolipídeos/análise , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Inflamação/induzido quimicamente , Material Particulado/análise , Aterosclerose/induzido quimicamente , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análiseRESUMO
Cardiovascular disease is the leading cause of death worldwide. Reperfusion therapy is vital to patient survival after a heart attack but can cause myocardial ischemia/reperfusion injury (MI/RI). Nitric oxide (NO) can ameliorate MI/RI and is a key molecule for drug development. However, reactive oxygen species (ROS) can easily oxidize NO to peroxynitrite, which causes secondary cardiomyocyte damage. Herein, L-arginine-loaded selenium-coated gold nanocages (AAS) are designed, synthesized, and modified with PCM (WLSEAGPVVTVRALRGTGSW) to obtain AASP, which targets cardiomyocytes, exhibits increased cellular uptake, and improves photoacoustic imaging in vitro and in vivo. AASP significantly inhibits oxygen glucose deprivation/reoxygenation (OGD/R)-induced H9C2 cell cytotoxicity and apoptosis. Mechanistic investigation revealed that AASP improves mitochondrial membrane potential (MMP), restores ATP synthase activity, blocks ROS generation, and prevents NO oxidation, and NO blocks ROS release by regulating the closing of the mitochondrial permeability transition pore (mPTP). AASP administration in vivo improves myocardial function, inhibits myocardial apoptosis and fibrosis, and ultimately attenuates MI/RI in rats by maintaining mitochondrial function and regulating NO signaling. AASP shows good safety and biocompatibility in vivo. This findings confirm the rational design of AASP, which can provide effective treatment for MI/RI.
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Traumatismo por Reperfusão Miocárdica , Ratos , Animais , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Óxido Nítrico/metabolismo , Espécies Reativas de Oxigênio/uso terapêutico , Ouro , Arginina/metabolismo , Mitocôndrias/metabolismoRESUMO
Kawasaki disease (KD) is a childhood vasculitis disease that is difficult to diagnose, and there is an urgent need for the identification of accurate and specific biomarkers. Here, we aimed to investigate metabolic alterations in patients with KD to determine novel diagnostic and prognostic biomarkers for KD. To this end, we performed untargeted metabolomics and found that several metabolic pathways were significantly enriched, including amino acid, lipid, and tryptophan metabolism, the latter of which we focused on particularly. Tryptophan-targeted metabolomics was conducted to explore the role of tryptophan metabolism in KD. The results showed that Trp and indole acetic acid (IAA) levels markedly decreased, and that l-kynurenine (Kyn) and kynurenic acid (Kyna) levels were considerably higher in patients with KD than in healthy controls. Changes in Trp, IAA, Kyn, and Kyna levels in a KD coronary arteritis mouse model were consistent with those in patients with KD. We further analyzed public single-cell RNA sequencing data of patients with KD and revealed that their peripheral blood mononuclear cells showed Aryl hydrocarbon receptor expression that was remarkably higher than that of healthy children. These results suggest that the Trp metabolic pathway is significantly altered in KD and that metabolic indicators may serve as novel diagnostic and therapeutic biomarkers for KD.
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Intracranial aneurysm is the leading cause of nontraumatic subarachnoid hemorrhage. Evaluating the unstable (rupture and growth) risk of aneurysms is helpful to guild decision-making for unruptured intracranial aneurysms (UIA). This study aimed to develop a model for risk stratification of UIA instability. The UIA patients from two prospective, longitudinal multicenter Chinese cohorts recruited from January 2017 to January 2022 were set as the derivation cohort and validation cohort. The primary endpoint was UIA instability, comprising aneurysm rupture, growth, or morphology change, during a 2-year follow-up. Intracranial aneurysm samples and corresponding serums from 20 patients were also collected. Metabolomics and cytokine profiling analysis were performed on the derivation cohort (758 single-UIA patients harboring 676 stable UIAs and 82 unstable UIAs). Oleic acid (OA), arachidonic acid (AA), interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were significantly dysregulated between stable and unstable UIAs. OA and AA exhibited the same dysregulated trends in serums and aneurysm tissues. The feature selection process demonstrated size ratio, irregular shape, OA, AA, IL-1ß, and TNF-α as features of UIA instability. A machine-learning stratification model (instability classifier) was constructed based on radiological features and biomarkers, with high accuracy to evaluate UIA instability risk (area under curve (AUC), 0.94). Within the validation cohort (492 single-UIA patients harboring 414 stable UIAs and 78 unstable UIAs), the instability classifier performed well to evaluate the risk of UIA instability (AUC, 0.89). Supplementation of OA and pharmacological inhibition of IL-1ß and TNF-α could prevent intracranial aneurysms from rupturing in rat models. This study revealed the markers of UIA instability and provided a risk stratification model, which may guide treatment decision-making for UIAs.
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Aneurisma Intracraniano , Humanos , Animais , Ratos , Aneurisma Intracraniano/diagnóstico , Estudos Prospectivos , População do Leste Asiático , Fator de Necrose Tumoral alfa , Medição de RiscoRESUMO
Nonalcoholic steatohepatitis (NASH) prevalence is rising with no pharmacotherapy approved. A major hurdle in NASH drug development is the poor translatability of preclinical studies to safe/effective clinical outcomes, and recent failures highlight a need to identify new targetable pathways. Dysregulated glycine metabolism has emerged as a causative factor and therapeutic target in NASH. Here, we report that the tripeptide DT-109 (Gly-Gly-Leu) dose-dependently attenuates steatohepatitis and fibrosis in mice. To enhance the probability of successful translation, we developed a nonhuman primate model that histologically and transcriptionally mimics human NASH. Applying a multiomics approach combining transcriptomics, proteomics, metabolomics, and metagenomics, we found that DT-109 reverses hepatic steatosis and prevents fibrosis progression in nonhuman primates, not only by stimulating fatty acid degradation and glutathione formation, as found in mice, but also by modulating microbial bile acid metabolism. Our studies describe a highly translatable NASH model and highlight the need for clinical evaluation of DT-109.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/metabolismo , Fibrose , Metabolismo dos Lipídeos , PrimatasRESUMO
Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.
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Carbono , Glucose , Animais , Camundongos , Glucose/metabolismo , Carbono/metabolismo , Ciclo do Ácido Cítrico , Ácido Láctico/metabolismo , LipídeosRESUMO
Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high risk of rupture. Because of its strong concealment, it is difficult to diagnose the disease in the early stage. At present, there are no effective drugs for the treatment of aneurysms. Surgical intervention and endovascular treatment are the only therapies. Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm, the specific mechanisms remain unclear. Researchers are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and treatment. To better understand aortic aneurysm, this review elaborates on the discovery history of aortic aneurysm, main classification and clinical manifestations, related molecular mechanisms, clinical cohort studies and animal models, with the ultimate goal of providing insights into the treatment of this devastating disease. The underlying problem with aneurysm disease is weakening of the aortic wall, leading to progressive dilation. If not treated in time, the aortic aneurysm eventually ruptures. An aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic wall. The disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.
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Aneurisma da Aorta Abdominal , Ruptura Aórtica , Animais , Humanos , Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/genética , Ruptura Aórtica/terapia , Estudos de CoortesRESUMO
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated death worldwide. Angiogenesis, the process of formation of new blood vessels, is required for cancer cells to obtain nutrients and oxygen. HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth, progression, invasion, and metastasis. Current anti-angiogenic therapies target mainly tyrosine kinases, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), and are considered effective strategies for HCC, particularly advanced HCC. However, because the survival benefits conferred by these anti-angiogenic therapies are modest, new anti-angiogenic targets must be identified. Several recent studies have determined the underlying molecular mechanisms, including pro-angiogenic factors secreted by HCC cells, the tumor microenvironment, and cancer stem cells. In this review, we summarize the roles of pro-angiogenic factors; the involvement of endothelial cells, hepatic stellate cells, tumor-associated macrophages, and tumor-associated neutrophils present in the tumor microenvironment; and the regulatory influence of cancer stem cells on angiogenesis in HCC. Furthermore, we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC. A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.
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Inibidores da Angiogênese , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neovascularização Patológica , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Células Endoteliais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/uso terapêuticoRESUMO
Abdominal aortic aneurysm (AAA) is a common vascular disease associated with significant phenotypic alterations in vascular smooth muscle cells (VSMCs). Gasdermin D (GSDMD) is a pore-forming effector of pyroptosis. In this study, the role of VSMC-specific GSDMD in the phenotypic alteration of VSMCs and AAA formation is determined. Single-cell transcriptome analyses reveal Gsdmd upregulation in aortic VSMCs in angiotensin (Ang) II-induced AAA. VSMC-specific Gsdmd deletion ameliorates Ang II-induced AAA in apolipoprotein E (ApoE)-/- mice. Using untargeted metabolomic analysis, it is found that putrescine is significantly reduced in the plasma and aortic tissues of VSMC-specific GSDMD deficient mice. High putrescine levels trigger a pro-inflammatory phenotype in VSMCs and increase susceptibility to Ang II-induced AAA formation in mice. In a population-based study, a high level of putrescine in plasma is associated with the risk of AAA (p < 2.2 × 10-16 ), consistent with the animal data. Mechanistically, GSDMD enhances endoplasmic reticulum stress-C/EBP homologous protein (CHOP) signaling, which in turn promotes the expression of ornithine decarboxylase 1 (ODC1), the enzyme responsible for increased putrescine levels. Treatment with the ODC1 inhibitor, difluoromethylornithine, reduces AAA formation in Ang II-infused ApoE-/- mice. The findings suggest that putrescine is a potential biomarker and target for AAA treatment.
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Aneurisma da Aorta Abdominal , Gasderminas , Músculo Liso Vascular , Putrescina , Animais , Camundongos , Aneurisma da Aorta Abdominal/induzido quimicamente , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Gasderminas/genética , Gasderminas/metabolismo , Músculo Liso Vascular/metabolismo , Ornitina Descarboxilase/metabolismo , Putrescina/efeitos adversos , Putrescina/metabolismo , Análise de Célula ÚnicaRESUMO
Over the past few decades, the treatment of atherosclerotic cardiovascular disease has mainly been through an LDL lowering strategy and treatments targeting other traditional risk factors for atherosclerosis, which has significantly reduced cardiovascular mortality. However, the overall benefit of targeting these risk factors has stagnated, and the discovery of new therapeutic targets for atherosclerosis remains a challenge. Accumulating evidence from clinical and animal experiments has revealed that the gut microbiome play a significant role in human health and disease, including cardiovascular diseases. The gut microbiome contribute to host health and disease through microbial composition and function. The gut microbiome function like an endocrine organ by generating bioactive metabolites that can impact atherosclerosis. In this review, we describe two gut microbial metabolites/pathways by which the gut affects atherosclerotic cardiovascular disease. On the one hand, we discuss the effects of trimethylamine oxide (TMAO), bile acids and aromatic amino acid metabolites on the development of atherosclerosis, and the protective effects of beneficial metabolites short chain amino acids and polyamines on atherosclerosis. On the other hand, we discuss novel therapeutic strategies for directly targeting gut microbial metabolites to improve cardiovascular outcomes. Reducing gut-derived TMAO levels and interfering with the bile acid receptor farnesoid X receptor (FXR) are new therapeutic strategies for atherosclerotic disease. Enzymes and receptors in gut microbiota metabolic pathways are potential new drug targets. We need solid insight into these underlying mechanisms to pave the way for therapeutic strategies targeting gut microbial metabolites/pathways for atherosclerotic cardiovascular disease.