TMAO promotes vascular endothelial cell pyroptosis via the LPEAT-mitophagy pathway.

Trimethylamine N-oxide (TMAO) is a novel risk factor for atherosclerosis, and its underlying regulatory mechanisms are under intensive investigation. Inflammation-related vascular endothelial damage is the major driver in atherogenic process. Pyroptosis, a type of proinflammatory programmed cell death, has been proved to promote the initiation and progression of atherosclerosis. In our study, we found that TMAO triggered endothelial cells excessive mitophagy, thereby facilitating pyroptosis. This process is mediated by the upexpression of phosphatidylethanolamine acyltransferase (LPEAT). These findings provide insights into TMAO-induced vascular endothelial cell damage and suggest that LPEAT may be a valuable target for the prevention and treatment of atherosclerosis.

Current Advances of Mitochondrial Dysfunction and Cardiovascular Disease and Promising Therapeutic Strategies.

Mitochondria are cellular power stations and essential organelles for maintaining cellular homeostasis. Dysfunctional mitochondria have emerged as a key factor in the occurrence and development of cardiovascular disease. This review focuses on advances in the relationship between mitochondrial dysfunction and cardiovascular diseases such as atherosclerosis, heart failure, myocardial ischemia reperfusion injury, and pulmonary arterial hypertension. The clinical value and challenges of mitochondria-targeted strategies, including mitochondria-targeted antioxidants, mitochondrial quality control modulators, mitochondrial function protectors, mitochondrial biogenesis promoters, and recently developed mitochondrial transplants, are also discussed.

Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT. METHODS: We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE-/- mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE-/- mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV). RESULTS: These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration. CONCLUSIONS: H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.

Low shear stress-induced endothelial mesenchymal transformation via the down-regulation of TET2.

Atherosclerotic cardiovascular disease is the major cause of death worldwide. Low shear stress plays key roles on the initiation and progression of atherosclerosis (As). However, its underlying mechanism remains unclear. In this study, the effect of low shear stress on endothelial mesenchymal transformation (EndMT) and its underlying mechanism were explored. Results showed that in cultured human umbilical vein endothelial cells, low shear stress down-regulated the expression of TET2 and promoted EndMT. Loss of TET2 promoted EndMT with the Wnt/ß-catenin signaling pathway. The enhancement in EndMT induced by low shear stress was attenuated by TET2 overexpression. In apoE-/- mice subjected to carotid artery local ligation, the EndMT and atherosclerotic lesions induced by low shear stress was attenuated by TET2 overexpression. Taken together, low shear stress promoted EndMT through the down-regulation of TET2, indicating that intervention with EndMT or the up-regulation of TET2 might be an alternative strategy for preventing As.

Trimethylamine N-oxide promotes apoE-/- mice atherosclerosis by inducing vascular endothelial cell pyroptosis via the SDHB/ROS pathway.

Trimethylamine N-oxide (TMAO) is produced from the phosphatidylcholine metabolism of gut flora and acts as a risk factor of cardiovascular disease. However, the underlying mechanisms for its proatherogenic action remain unclear. This study aimed to observe the effect of TMAO on endothelial cell pyroptosis and explore the underlying mechanisms. Our results showed that TMAO promoted the progression of atherosclerotic lesions in apolipoprotein E-deficient (apoE-/- ) mice fed a high-fat diet. Pyroptosis and succinate dehydrogenase complex subunit B (SDHB) upregulation were detected in the vascular endothelial cells of apoE-/- mice and in cultured human umbilical vein endothelial cells (HUVECs) treated with TMAO. Overexpression of SDHB in HUVECs enhanced pyroptosis and impaired mitochondria and high reactive oxygen species (ROS) level. Pyroptosis in the SDHB overexpression of endothelial cells was inhibited by the ROS scavenger NAC. In summary, TMAO promotes vascular endothelial cell pyroptosis via ROS induced through SDHB upregulation, thereby contributing to the progression of atherosclerotic lesions.

Hydrogen Sulfide Switch Phenomenon Regulating Autophagy in Cardiovascular Diseases.

Hydrogen sulfide (H2S), a novel gaseous signaling molecule, is a vital physiological signal in mammals. H2S protects the cardiovascular system via modulation of vasodilation, vascular remodeling, and inhibition of vascular calcification, and also has anti-atherosclerosis properties. Autophagy is a lysosomal-mediated intracellular degradation mechanism for excessive or abnormal proteins and lipids. The contribution of autophagy to normal and disease-state cell physiology is extremely complicated. Autophagy acts as a double-edged sword in the cardiovascular system. It can defend against damage to cells caused by environmental changes and it can also induce active cell death under certain conditions. In recent years, accumulating evidence indicates that H2S can up- or downregulate autophagy in many pathological processes, thereby switching from a harmful to a beneficial role. In this review, we summarize progress on understanding the mechanism by which H2S regulates autophagy in cardiovascular disease. We also discuss a H2S switch phenomenon that regulates autophagy and provides protection in cardiovascular diseases.

miR-23b-3p and miR-125b-5p downregulate apo(a) expression by targeting Ets1 in HepG2 cells.

High concentrations of plasma lipoprotein(a) [Lp(a)] have been inferred to be an independent risk factor for cardiovascular and cerebrovascular diseases, such as coronary artery diseases, restenosis, and stroke. Apolipoprotein(a) [apo(a)] is one of the most important components of Lp(a) and contributes greatly to the increased concentration of plasma Lp(a). As a critical positive transacting factor of apo(a) gene, Ets1 has been proven as a target gene of several miRNAs, such as miR-193b, miR-125b-5p, miR-200b, miR-1, and miR-499. In this study, a series of experiments on miRNAs and relative miRNAs inhibitor delivered HepG2 cells were conducted, and two miRNAs that downregulate the apo(a) by targeting the 3'-UTR of Ets1 were identified. Results showed that apo(a) and Ets1 were differentially expressed in SMMC7721 and HepG2 cell lines. Meanwhile, apo(a) and Ets1 were inversely correlated with several hepatic endogenous miRNAs, such as miR-125b-5p, miR-23b-3p, miR-26a-5p, and miR-423-5p, which were predicted to bind to Ets1. Results show that miR-125b-5p and miR-23b-3p mimics could inhibit the synthesis of apo(a) by directly targeting Ets1 in HepG2, thereby reducing the plasma Lp (a) concentration.

H2 S inhibits apo(a) expression and secretion through PKCα/FXR and Akt/HNF4α pathways in HepG2 cells.

Lipoprotein(a) [Lp(a)] is a strong genetic risk factor for coronary heart diseases. However, the metabolism of this protein remains poorly understood. Efficient and specific drugs that can decrease high plasma levels of Lp(a) have not been developed yet. Hydrogen sulfide (H2 S), a member of the gas transmitter family, performs important biological actions, including protection against cardiovascular diseases and maintenance of the lipid metabolism equilibrium in hepatocytes and adipocytes. In this study, we investigated the possible molecular mechanism of H2 S that influences apolipoprotein(a) [apo(a)] biosynthesis. We also determined the effects of H2 S on apo(a) expression and secretion in HepG2 cells as well as the underlying mechanisms. Results showed that H2 S significantly inhibited the expression and secretion levels of apo(a). These effects were attenuated by the PKCα inhibitor and FXR siRNA. H2 S also reduced HNF4α expression and enhanced FXR expression. The Akt inhibitor partially reversed H2 S-induced inhibition of apo(a) and HNF4α expression and apo(a) secretion. This study reveals that H2 S suppressed apo(a) expression and secretion via the PKCα-FXR and PI3K/Akt-HNF4α pathways.

TMAO induces pyroptosis of vascular endothelial cells and atherosclerosis in ApoE-/- mice via MBOAT2-mediated endoplasmic reticulum stress.

Trimethylamine N-oxide (TMAO), a metabolite produced by intestinal flora, is recognized as an independent risk factor for atherosclerosis and atherosclerotic cardiovascular diseases. However, the underlying mechanism remains poorly understood. Here, we showed that dietary TMAO supplementation accelerates atherosclerosis in ApoE-/- mice. Pyroptosis and the expression of phospholipid-modifying enzyme MBOAT2 were increased in endothelial cells within atherosclerotic lesions. Genetic upregulation of MBOAT2 via adeno-associated virus with endothelium-specific promoter results in increased atherosclerotic lesions in ApoE-/- mice. Mechanistically, the overexpression of MBOAT2 disrupted glycerophospholipid metabolism and induced endothelial cell pyroptosis in an Endoplasmic reticulum stress-dependent manner. These data reveal that TMAO promotes endothelial cell pyroptosis and the progression of atherosclerotic lesions through the upregulation of MBOAT2, indicating that MBOAT2 is a promising therapeutic target for atherosclerosis.

Long-term resistance to fracture and/or corrosion of the nitinol wires of the talent stent-graft: observations from a series of explanted devices.

The biodurability of the Nitinol wires used in stent-grafts retrieved from reoperations and autopsy was analyzed to assess the possible causes of fracture and/or corrosion of the stents. The Nitinol wires of six explanted devices presented a corrosion-free surface after in vivo service. The drawing lines in the control wires were still present, but neither burrs nor flakes were observed. Pits and crevices were rare, but some shallow ones were present. Some abrasions of the surfaces of the Nitinol wires were also observed. The chemical composition of the explanted devices showed the presence of organic contamination that covered the thick layer of titanium oxide before reaching the Nitinol itself. The durability of the Nitinol employed in the manufacture of the Talent stent-grafts was confirmed; the results of this study show the Nitinol to be resistant to corrosion. We have also concluded that the fractures of the Nitinol wires in two devices were unique adverse incidents caused by compression and bending related to the sharp angle of the Nitinol wires.

Fatigue and/or failure phenomena observed in the fabric of stent-grafts explanted after adverse events.

In this study, we aimed to investigate changes to the fabric of Talent stent-grafts following implantation of aortic endografts and to determine the possible causes of fatigue and/or failure of the grafts. Six devices were explanted at reoperation (N=5) and autopsy (N=1). Selected segments were assessed nondestructively by gross observation and destructively by analyzing textile characteristics and chemical properties. All of the devices showed a 4/4 twill woven fabric of monofilament polyester. These devices, explanted at reoperation and autopsy, presented different levels of fatigue and/or failure. Numerous holes were found in the fabric of two devices. The minor damage caused by the passage of the sutures through the weave to fasten the Nitinol wires did not progress significantly over time. The sutures remained relatively intact, except for some distortions. The main failure mode was the abrasion of the yarns at the apices of adjacent Nitinol stents. In two devices, this abrasion resulted in fraying of the yarns and holes in the fabric tubes. This short series of explanted devices provides evidence of damage to polyester fabric used in aortic endografts and raises questions regarding their resistance to abrasion and the risk of endoleak associated with monofilament fabric yarn.

Absence of tissue ingrowth through the textile fabric in a series of explanted clinic stent-grafts.

Using the retrieved devices from one autopsy and five reoperations, the biocompatibility of explanted Talent stent-grafts was investigated to highlight the capacity of the fabric to act as an effective scaffold to regenerate a blood conduit. The autopsy device was encapsulated both internally and externally, but the capsules did not penetrate through the fabric structure. The reoperation devices showed discrete patches of compact fibrin and irregularly scattered mural thrombi. Positive staining of α-actin, tissue plasminogen activator (tPA), urokinase (uPA), urokinase receptor (uPAR), and urokinase inhibitors (PAI 1, PAI 2, PAI 3, and protease nexin), and D-dimer was more frequently identified in the autopsy sample than in the reoperation samples. This preliminary assessment shows that the stent-graft retrieved during autopsy was better healed than those explanted at reoperation.

Atherosclerosis: From the Disruption of Mitochondrial Membrane Potential to the Potential Interventional Strategies.

Atherosclerosis (AS) is the major factor of cardiovascular disease (CVD) and is characterized by a progressive and chronic inflammatory process in the arterial wall. Recent studies have shown that disruption of the mitochondrial membrane potential (deltapsi (m)) directly affects the electron transport chain (ETC), which in turn leads to oxidative stress, and furthermore, its alteration leads to apoptosis and activation of the NLRP3 inflammasome, thereby promoting the development of AS. Here, this review describes how deltapsi (m) contributes to the development of AS by mediating oxidative stress, apoptosis, and NLRP3 inflammasome activation, and potential AS intervention strategies by targeting oxidative stress, apoptosis, and NLRP3 inflammasome activation induced by deltapsi (m).

Mitophagy: Critical Role in Atherosclerosis Progression.

Autophagy maintains intracellular homeostasis in the cardiovascular system, including in cardiomyocytes, endothelial cells (ECs), and arterial smooth muscle cells. Mitophagy, a selective autophagy that specifically removes damaged and dysfunctional mitochondria, is particularly important for cardiovascular homeostasis. Dysfunctional mitophagy contributes to cardiovascular disease, particularly atherosclerosis (AS). This review focuses on the advances of regulator mechanisms of mitophagy and its potential roles in AS. The findings are beneficial to understanding the pathological processes of atherosclerotic lesions and provide new ideas for the prevention and clinical treatment of AS.

Succinate: A Novel Mediator to Promote Atherosclerotic Lesion Progression.

Succinate is an important intermediate product of mitochondrial energy metabolism. Recent studies revealed that beyond its known traditional metabolic functions, succinate plays important roles in signal transduction, immunity, inflammation, and posttranslational modification. Recent studies showed that patients and mouse models with cardiovascular disease have high levels of serum succinate and succinate accumulation. Atherosclerosis (As) is the pathological basis of cardiovascular and peripheral vascular diseases, such as coronary heart disease, cerebral infarction, and peripheral vascular disease, and is a major factor affecting human health. This article reviews the progression of succinate in As diseases and its underlying mechanisms.

Krebs Cycle Rewired: Driver of Atherosclerosis Progression?

The tricarboxylic acid (TCA) cycle is the center of energy metabolism in eukaryotic cells and is dynamically adjusted according to the energy needs of cells. Macrophages are activated by inflammatory stimuli, and then two breakpoints in TCA cycle lead to the accumulation of intermediates. Atherosclerosis is a chronic inflammatory process. Here, the "non-metabolic" signaling functions of TCA cycle intermediates in the macrophage under inflammatory stimulation and the role of intermediates in the progression of atherosclerosis are discussed.

Development of hydrogen sulfide donors for anti-atherosclerosis therapeutics research: Challenges and future priorities.

Hydrogen sulfide (H2S), a gas transmitter found in eukaryotic organisms, plays an essential role in several physiological processes. H2S is one of the three primary biological gas transmission signaling mediators, along with nitric oxide and carbon monoxide. Several animal and in vitro experiments have indicated that H2S can prevent coronary endothelial mesenchymal transition, reduce the expression of endothelial cell adhesion molecules, and stabilize intravascular plaques, suggesting its potential role in the treatment of atherosclerosis (AS). H2S donors are compounds that can release H2S under certain circumstances. Development of highly targeted H2S donors is a key imperative as these can allow for in-depth evaluation of the anti-atherosclerotic effects of exogenous H2S. More importantly, identification of an optimal H2S donor is critical for the creation of H2S anti-atherosclerotic prodrugs. In this review, we discuss a wide range of H2S donors with anti-AS potential along with their respective transport pathways and design-related limitations. We also discuss the utilization of nano-synthetic technologies to manufacture H2S donors. This innovative and effective design example sheds new light on the production of highly targeted H2S donors.

Detailed analysis of a series of explanted Talent AAA stent-grafts: biofunctionality assessment.

Six Talent stent-grafts were harvested at reoperations (N=5) and autopsy (N=1). The explants were observed nondestructively, including gross morphology, X-rays, CT scans and closed pressure system analysis. The Nitinol frames in three devices harvested at reoperations and another harvested at autopsy were intact. One had a stent fracture of the proximal bare stent, and one had a wire fracture of a thin proximal external supporting stent as well as a hole in the fabric just above the bifurcation. For the three devices structurally intact, reoperations were performed for a type 1A endoleak (one patient) and aorto-enteric fistulas (two patients). The healing characteristics were poor or absent. The fabric in the main body of the grafts harvested after aorto-enteric fistula was devoid of biological deposits. Two of the grafts harvested at reoperation demonstrated fabric holes of up to 4 mm 2. The device obtained at autopsy showed an almost continuous internal capsule with variable thickness. The luminal surface was smooth, but the capsule detached easily. The devices explanted at reoperations showed various levels of impaired biofunctionality associated with adverse outcomes. The stent-graft retrieved from autopsy was intact.

PD-1/PD-L1 immune checkpoints: Tumor vs atherosclerotic progression.

Immunotherapy has become one of the most attraction cancer therapy strategies. The PD-1/PD-L1 pathway plays key roles in immune responses and autoimmunity by regulating T cell activity. Overactivation of this pathway dampens T cell and immune function, which allows tumor cells immune escape. Antibody or inhibitors of PD-1/PD-L1 immune targets have been implicated in clinic anti-cancer therapy and gain great clinic outcoming for their high efficiency. However, recent studies showed that the PD-1/PD-L1 immunotherapy in some tumor patients was found to accelerate T cell-driven inflammatory and the progression of atherosclerotic lesions. This article reviews the research progression of PD-1/PD-L1 in tumors and atherosclerosis, and the possible mechanisms of anti-PD-1/PD-L1 immunotherapy increasing the risk of atherosclerotic lesions.

Research Progress on the Role of Intermediate Filament Vimentin in Atherosclerosis.

The cytoskeleton is a biopolymer network composed of intermediate filaments, actin, and microtubules, which is the main mechanical structure of cells. Vimentin is an intermediate filament protein that regulates the mechanical and contractile properties of cells, thereby reflecting their mechanical properties. In recent years, the "nonmechanical function" of vimentin inside and outside of cells has attracted extensive attention. The content of vimentin in atherosclerotic plaques is increased, and the serum secretion of vimentin in patients with coronary heart disease is remarkably increased. In this review, the mechanistic and nonmechanistic roles of vimentin in atherosclerosis progression were summarized on the basis of current studies.