Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis.

Endothelial injury and dysfunction in the artery wall fuel the process of atherosclerosis. As a key epigenetic regulator, Ash2l (Absent, small, or homeotic-Like 2) is involved in regulating vascular injury and its complications. However, the role of Ash2l in atherosclerosis has not yet been fully elucidated. Here, we found increased Ash2l expression in high-cholesterol diet-fed ApoE-/- mice and oxidized LDL (oxLDL) treated endothelial cells (ECs). Furthermore, Ash2l promoted the scavenger receptors transcription by catalyzing histone H3 lysine 4 (H3K4) trimethylation at the promoter region of transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) and triggered the activation of the pro-inflammatory nuclear factor-kappa B (NF-κB) by enhancing interaction between CD36 and toll-like receptor 4 (TLR4). Meanwhile, enhanced expression of scavenger receptors drove more oxLDL uptake by ECs. In vivo studies revealed that ECs-specific Ash2l knockdown reduced atherosclerotic lesion formation and promoted fibrous cap stability in the aorta of ApoE-/- mice, which was partly associated with a reduced endothelial activation by suppressing scavenger receptors and the uptake of lipids by ECs. Collectively, our findings identify Ash2l as a novel regulator that mediates endothelial injury and atherosclerosis. Targeting Ash2l may provide valuable insights for developing novel therapeutic candidates for atherosclerosis.

Novel nano-drug delivery system for natural products and their application.

The development of natural products for potential new drugs faces obstacles such as unknown mechanisms, poor solubility, and limited bioavailability, which limit the broadened applicability of natural products. Therefore, there is a need for advanced pharmaceutical formulations of active compounds or natural products. In recent years, novel nano-drug delivery systems (NDDS) for natural products, including nanosuspensions, nanoliposomes, micelle, microemulsions/self-microemulsions, nanocapsules, and solid lipid nanoparticles, have been developed to improve solubility, bioavailability, and tissue distribution as well as for prolonged retention and enhanced permeation. Here, we updated the NDDS delivery systems used for natural products with the potential enhancement in therapeutic efficiency observed with nano-delivery systems.

Neutrophil-Mimetic, ROS Responsive, and Oxygen Generating Nanovesicles for Targeted Interventions of Refractory Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is the most prevalent inflammatory joint disease worldwide, leading to irreversible disability and even mortality. Unfortunately, current treatment regimens fail to cure RA due to low therapeutic responses and off-target side effects. Herein, a neutrophil membrane-cloaked, natural anti-arthritic agent leonurine (Leo), and catalase (CAT) co-loaded nanoliposomal system (Leo@CAT@NM-Lipo) is constructed to remodel the hostile microenvironment for RA remission. Due to the inflammation tropism inherited from neutrophils, Leo@CAT@NM-Lipo can target and accumulate in the inflamed joint cavity where high-level ROS can be catalyzed into oxygen by CAT to simultaneously accelerate the drug release and alleviate hypoxia at the lesion site. Besides, the neutrophil membrane camouflaging also enhances the anti-inflammatory potentials of Leo@CAT@NM-Lipo by robustly absorbing pro-arthritogenic cytokines and chemokines. Consequently, Leo@CAT@NM-Lipo successfully alleviated paw swelling, reduced arthritis score, mitigated bone and cartilage damage, and reversed multiple organ dysfunctions in adjuvant-induced arthritis rats (AIA) rats by synergistic effects of macrophage polarization, inflammation resolution, ROS scavenging, and hypoxia relief. Furthermore, Leo@CAT@NM-Lipo manifested excellent biocompatibility both at the cellular and animal levels. Taken together, the study provided a neutrophil-mimetic and ROS responsive nanoplatform for targeted RA therapy and represented a promising paradigm for the treatment of a variety of inflammation-dominated diseases.

Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease phenotypes which start with simple steatosis and lipid accumulation in the hepatocytes - a typical histological lesions characteristic. It may progress to non-alcoholic steatohepatitis (NASH) that is characterized by hepatic inflammation and/or fibrosis and subsequent onset of NAFLD-related cirrhosis and hepatocellular carcinoma (HCC). Due to the central role of the liver in metabolism, NAFLD is regarded as a result of and contribution to the metabolic abnormalities seen in the metabolic syndrome. Peroxisome proliferator-activated receptors (PPARs) has three subtypes, which govern the expression of genes responsible for energy metabolism, cellular development, inflammation, and differentiation. The agonists of PPARα, such as fenofibrate and clofibrate, have been used as lipid-lowering drugs in clinical practice. Thiazolidinediones (TZDs) - ligands of PPARγ, such as rosiglitazone and pioglitazone, are also used in the treatment of type 2 diabetes (T2D) with insulin resistance (IR). Increasing evidence suggests that PPARß/δ agonists have potential therapeutic effects in improving insulin sensitivity and lipid metabolism disorders. In addition, PPARs ligands have been considered as potential therapeutic drugs for hypertension, atherosclerosis (AS) or diabetic nephropathy. Their crucial biological roles dictate the significance of PPARs-targeting in medical research and drug discovery. Here, it reviews the biological activities, ligand selectivity and biological functions of the PPARs family, and discusses the relationship between PPARs and the pathogenesis of NAFLD and metabolic syndrome. This will open new possibilities for PPARs application in medicine, and provide a new idea for the treatment of fatty liver and related diseases.

From Bench to Bedside: What Do We Know about Imidazothiazole Derivatives So Far?

Imidazothiazole derivatives are becoming increasingly important in therapeutic use due to their outstanding physiological activities. Recently, applying imidazothiazole as the core, researchers have synthesized a series of derivatives with biological effects such as antitumor, anti-infection, anti-inflammatory and antioxidant effects. In this review, we summarize the main pharmacological effects and pharmacological mechanisms of imidazothiazole derivates; the contents summarized herein are intended to advance the research and rational development of imidazothiazole-based drugs in the future.

HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3.

BACKGROUND: Histone deacetylases (HDACs) have been shown to be involved in tumorigenesis, but their precise role and molecular mechanisms in gastric cancer (GC) have not yet been fully elucidated. METHODS: Bioinformatics screening analysis, qRT-PCR, and immunohistochemistry (IHC) were used to identify the expression of HDAC4 in GC. In vitro and in vivo functional assays illustrated the biological function of HDAC4. RNA-seq, GSEA pathway analysis, and western blot revealed that HDAC4 activated p38 MAPK signalling. Immunofluorescence, western blot, and IHC verified the effect of HDAC4 on autophagy. ChIP and dual-luciferase reporter assays demonstrated that the transcriptional regulation mechanism of HDAC4 and ATG4B. RESULTS: HDAC4 is upregulated in GC and correlates with poor prognosis. In vitro and in vivo assays showed that HDAC4 contributes to the malignant phenotype of GC cells. HDAC4 inhibited the MEF2A-driven transcription of ATG4B and prevented MEKK3 from p62-dependent autophagic degradation, thus activating p38 MAPK signalling. Reciprocally, the downstream transcription factor USF1 enhanced HDAC4 expression by regulating HDAC4 promoter activity, forming a positive feedback loop and continuously stimulating HDAC4 expression and p38 MAPK signalling activation. CONCLUSION: HDAC4 plays an oncogenic role in GC, and HDAC4-based targeted therapy would represent a novel strategy for GC treatment.

Hirsutine ameliorates hepatic and cardiac insulin resistance in high-fat diet-induced diabetic mice and in vitro models.

Closely associated with type 2 diabetes mellitus (T2DM), hepatic steatosis and cardiac hypertrophy resulting from chronic excess intake can exacerbate insulin resistance (IR). The current study aims to investigate the pharmacological effects of hirsutine, one indole alkaloid isolated from Uncaria rhynchophylla, on improving hepatic and cardiac IR, and elucidate the underlying mechanism. T2DM and IR in vivo were established by high-fat diet (HFD) feeding for 3 months in C57BL/6 J mice. In vitro IR models were induced by high-glucose and high-insulin (HGHI) incubation in HepG2 and H9c2 cells. Hirsutine administration for 8 weeks improved HFD-induced peripheral hyperglycemia, glucose tolerance and IR by OGTT and ITT assays, and simultaneously attenuated hepatic steatosis and cardiac hypertrophy by pathological observation. The impaired p-Akt expression was activated by hirsutine in liver and heart tissues of HFD mice, and also in the models in vitro. Hirsutine exhibited the effects on enhancing glucose consumption and uptake in IR cell models via activating phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which was blocked by PI3K inhibitor LY294002. Moreover, the effect of hirsutine on promoting glucose uptake and GLUT4 expression in HGHI H9c2 cells was also prevented by Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Enhancement of glycolysis might be another factor of hirsutine showing its effects on glycemic control. Collectively, it was uncovered that hirsutine might exert beneficial effects on regulating glucose homeostasis, thus improving hepatic and cardiac IR, and could be a promising compound for treating diet-induced T2DM.

H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation.

[Figure: see text].

[Effect and mechanism of leonurine on pressure overload-induced cardiac hypertrophy in rats].

To investigate the effects of leonurine(Leo) on abdominal aortic constriction(AAC)-induced cardiac hypertrophy in rats and its mechanism. A rat model of pressure overload-induced cardiac hypertrophy was established by AAC method. After 27-d intervention with high-dose(30 mg·kg~(-1)) and low-dose(15 mg·kg~(-1)) Leo or positive control drug losartan(5 mg·kg~(-1)), the cardiac function was evaluated by hemodynamic method, followed by the recording of left ventricular systolic pressure(LVSP), left ventricular end-diastolic pressure(LVESP), as well as the maximum rate of increase and decrease in left ventricular pressure(±dp/dt_(max)). The degree of left ventricular hypertrophy was assessed based on heart weight index(HWI) and left ventricular mass index(LVWI). Myocardial tissue changes and the myocardial cell diameter(MD) were measured after hematoxylin-eosin(HE) staining. The contents of angiotensin Ⅱ(AngⅡ) and angiotensin Ⅱ type 1 receptor(AT1 R) in myocardial tissue were detected by ELISA. The level of Ca~(2+) in myocardial tissue was determined by colorimetry. The protein expression levels of phospholipase C(PLC), inositol triphosphate(IP3), AngⅡ, and AT1 R were assayed by Western blot. Real-time quantitative PCR(qRT-PCR) was employed to determine the mRNA expression levels of ß-myosin heavy chain(ß-MHC), atrial natriuretic factor(ANF), AngⅡ, and AT1 R. Compared with the model group, Leo decreased the LVSP, LVEDP, HWI, LVWI and MD values, but increased ±dp/dt_(max) of the left ventricle. Meanwhile, it improved the pathological morphology of myocardial tissue, reduced cardiac hypertrophy, edema, and inflammatory cell infiltration, decreased the protein expression levels of PLC, IP3, AngⅡ, AT1 R, as well as the mRNA expression levels of ß-MHC, ANF, AngⅡ, AT1 R, c-fos, and c-Myc in myocardial tissue. Leo inhibited AAC-induced cardiac hypertrophy possibly by influencing the RAS system.

The gut microbiome as non-invasive biomarkers for identifying overweight people at risk for osteoarthritis.

OBJECTIVE: To evaluate the potential for identifying overweight people at risk for osteoarthritis from a gut microbiome biomarker. BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis, affecting millions of people worldwide. Being overweight increases the load placed on the joints such as the knee, which increases stress and could hasten the breakdown of cartilage. Identifying overweight people at risk for osteoarthritis remains a challenge. However, emerging evidence indicates that microbial dysbiosis in the human gut might play an important role in many inflammatory diseases. Considering the role of inflammation in OA development, analysis of the gut microbiome might be a potential non-invasive tool for overweight individuals to evaluate their risk for OA. RESULTS: In this prospective study, we collected 182 stool samples from overweight OA patients (n = 86) and overweight normal people (n = 96) (25 kg/m2

The Cardiovascular Effects of Hydrogen Sulfide: The Epigenetic Mechanisms.

Hydrogen sulfide (H2S), known as a gas signal molecule, plays an important role in the development of cardiovascular diseases (CVD) through mechanisms such as angiogenesis, vasodilation, and anti-vascular endothelial cell senescence. Current studies have shown that H2S can regulate cardiac function through epigenetic regulation. The regulation has opened up a new avenue for the study of CVD development mechanism and H2S related drug discoveries.

Hydrogen Sulfide and the Immune System.

Hydrogen sulfide (H2S) is the "third gasotransmitter" recognized alongside nitric oxide (NO) and carbon monoxide (CO). H2S exhibits an array of biological effects in mammalian cells as revealed by studies showing important roles in the cardiovascular system, in cell signalling processes, post-translational modifications and in the immune system. Regarding the latter, using pharmacological and genetic approaches scientists have shown this molecule to have both pro- and anti-inflammatory effects in mammalian systems. The anti-inflammatory effects of H2S appeared to be due to its inhibitory action on the nuclear factor kappa beta signalling pathway; NF-kB representing a transcription factor involved in the regulation pro-inflammatory mediators like nitric oxide, prostaglandins, and cytokines. In contrast, results from several animal model describe a more complicated picture and report on pro-inflammatory effects linked to exposure to this molecule; linked to dosage used and point of administration of this molecule. Overall, roles for H2S in several inflammatory diseases spanning arthritis, atherosclerosis, sepsis, and asthma have been described by researchers. In light this work fascinating research, this chapter will cover H2S biology and its many roles in the immune system.

Hydrogen Sulfide: a Novel Immunoinflammatory Regulator in Rheumatoid Arthritis.

Hydrogen sulfide (H2S), an endogenous, gaseous, signaling transmitter, has been shown to have vasodilative, anti-oxidative, anti-inflammatory, and cytoprotective activities. Increasing evidence also indicates that H2S can suppress the production of inflammatory mediators by immune cells, for example, T cells and macrophages. Inflammation is closely related to an immune response in several diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and cancer. Considering these biological effects of H2S, a potential role in the treatment of immune-related RA is being exploited. In the present review, we will provide an overview of the therapeutic potential of H2S in RA treatment.

eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization.

Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system and prevents the early progression of atherosclerosis; however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. Apolipoprotein E gene-deficient mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness and collagen content while decreasing the population of CD68-positive cells. Enhanced plaque stability by LEO was associated with the nitric oxide synthase (NOS)-nitric oxide (NO) system. LEO restored the balance between endothelial NOS(E)- and inducible NOS(iNOS)-derived NO production; suppressed the NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque, including cytokine interleukin 6; and downregulated the expression of adhesion molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with oxidized low-density lipoprotein-challenged human umbilical vein endothelial cells revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO system and mitigated inflammation contribute to the plaque-stabilizing effect of LEO. SIGNIFICANCE STATEMENT: LEO restored the balance between endothelial NOS and inducible NOS in NO production and inhibited excessive inflammation in atherosclerotic "unstable" and rupture-prone plaques in apolipoprotein E gene-deficient mice. The protective effect of LEO for stabilizing atherosclerotic plaques was due to improved collagen content, increased fibrous cap thickness, and decreased accumulation of macrophages/foam cells. So far, LEO has passed the safety and feasibility test of phase I clinical trial.

Biochemical indicators of coronavirus disease 2019 exacerbation and the clinical implications.

Coronavirus Disease 2019 (COVID-19) has sparked a global pandemic, affecting more than 4 million people worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute lung injury (ALI) and even acute respiratory distress syndrome (ARDS); with a fatality of 7.0 %. Accumulating evidence suggested that the progression of COVID-19 is associated with lymphopenia and excessive inflammation, and a subset of severe cases might exhibit cytokine storm triggered by secondary hemophagocytic lymphohistiocytosis (sHLH). Furthermore, secondary bacterial infection may contribute to the exacerbation of COVID-19. We recommend using both IL-10 and IL-6 as the indicators of cytokine storm, and monitoring the elevation of procalcitonin (PCT) as an alert for initiating antibacterial agents. Understanding the dynamic progression of SARS-CoV-2 infection is crucial to determine an effective treatment strategy to reduce the rising mortality of this global pandemic.

Combinational applicaton of silybin and tangeretin attenuates the progression of non-alcoholic steatohepatitis (NASH) in mice via modulating lipid metabolism.

Silybin (SB) is widely used to treat chronic liver diseases, especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR, PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH. Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH.

ZYZ-803, a novel hydrogen sulfide-nitric oxide conjugated donor, promotes angiogenesis via cross-talk between STAT3 and CaMKII.

Endothelial angiogenesis plays a vital role in recovery from chronic ischemic injuries. ZYZ-803 is a hybrid donor of hydrogen sulfide (H2S) and nitric oxide (NO). Previous studies showed that ZYZ-803 stimulated endothelial cell angiogenesis both in vitro and in vivo. In this study, we investigated whether the signal transducer and activator of transcription 3 (STAT3) and Ca2+/CaM-dependent protein kinase II (CaMKII) signaling was involved in ZYZ-803-induced angiogenesis. Treatment with ZYZ-803 (1 µM) significantly increased the phosphorylation of STAT3 (Tyr705) and CaMKII (Thr286) in human umbilical vein endothelial cells (HUVECs), these two effects had a similar time course. Pretreatment with WP1066 (STAT3 inhibitor) or KN93 (CAMKII inhibitor) blocked ZYZ-803-induced STAT3/CAMKII activation and significantly suppressed the proliferation and migration of HUVECs. In addition, pretreatment with the inhibitors significantly decreased ZYZ-803-induced tube formations along with the outgrowths of branch-like microvessels in aortic rings. In the mice with femoral artery ligation, administration of ZYZ-803 significantly increased the blood perfusion and vascular density in the hind limb, whereas co-administration of WP1066 or KN93 abrogated ZYZ-803-induced angiogenesis. By using STAT3 siRNA, we further explored the cross-talk between STAT3 and CaMKII in ZYZ-803-induced angiogenesis. We found that STAT3 knockdown suppressed ZYZ-803-induced HUVEC angiogenesis and affected CaMKII expression. ZYZ-803 treatment markedly enhanced the interaction between CaMKII and STAT3. ZYZ-803 treatment induced the nuclear translocation of STAT3. We demonstrated that both STAT3 and CaMKII functioned as positive regulators in ZYZ-803-induced endothelial angiogenesis and STAT3 was important in ZYZ-803-induced CaMKII activation, which highlights the beneficial role of ZYZ-803 in STAT3/CaMKII-related cardiovascular diseases.

The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities.

December 2019 saw the emergence of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has spread across the globe. The high infectivity and ongoing mortality of SARS-CoV-2 emphasize the demand of drug discovery. Angiotensin-converting enzyme II (ACE2) is the functional receptor for SARS-CoV-2 entry into host cells. ACE2 exists as a membrane-bound protein on major viral target pulmonary epithelial cells, and its peptidase domain (PD) interacts SARS-CoV-2 spike protein with higher affinity. Therefore, targeting ACE2 is an important pharmacological intervention for a SARS-CoV-2 infection. In this review, we described the two-way switch role of ACE2 in the treatment of novel coronavirus pneumonia and underlying comorbidities, and discussed the potential effect of the ACE inhibitor and angiotensin receptor blocker on a hypertension patient with the SARS-CoV-2 infection. In addition, we analyzed the S-protein-binding site on ACE2 and suggested that blocking hot spot-31 and hot spot-353 on ACE2 could be a therapeutic strategy for preventing the spread of SARS-CoV-2. Besides, the recombinant ACE2 protein could be another potential treatment option for SARS-CoV-2 induced acute severe lung failure. This review could provide beneficial information for the development of anti-SARS-CoV-2 agents via targeting ACE2 and the clinical usage of renin-angiotensin system (RAS) drugs for novel coronavirus pneumonia treatment.

Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

Hydrogen sulfide stabilizes atherosclerotic plaques in apolipoprotein E knockout mice.

Hydrogen sulfide gas (H2S) has protective effects in the cardiovascular system that includes preventing the development of atherosclerosis when tested in several in vivo models. Plaque instability is a major risk factor for thromboembolism, myocardial infarction, and stroke, so we examined if H2S can promote plaque stability and the potential underlying mechanisms. Apolipoprotein E knockout mice fed an atherogenic diet were administered the exogenous H2S donor sodium hydrosulfide (NaHS) or pravastatin as a positive control daily for 14 weeks. NaHS significantly enhanced plaque stability by increasing fibrous cap thickness and collagen content compared to vehicle-treated controls. NaHS treatment also reduced blood lipid levels and plaque formation. Preservation of plaque stability by NaHS was associated with reductions in vascular smooth muscle cells (VSMCs) apoptosis and expression of the collagen-degrading enzyme matrix metallopeptidase-9 (MMP-9) in plaque. While pravastatin also increased fibrous cap thickness and reduced VSMC apoptosis, but did not enhance plaque collagen or reduce MMP-9 significantly, suggesting distinct mechanisms of plaque stabilization. in vitro, NaHS also decreased MMP-9 expression in macrophages stimulated with tumor necrosis factor-α by inhibiting ERK/JNK phosphorylation and activator protein 1 nuclear translocation. Moreover, H2S reduced caspase-3/9 activity, Bax/Bcl-2 ratio, and LOX-1 mRNA expression in VSMCs stimulated with oxidized low-density lipoprotein. These results suggest that H2S enhances plaque stability and protects against atherogenesis by increasing plaque collagen content and VSMC count. In conclusion, H2S exerts protective effects against atherogenesis at least partly by stabilizing atherosclerotic plaque.