The Effect and Mechanism of Oleanolic Acid in the Treatment of Metabolic Syndrome and Related Cardiovascular Diseases.

Metabolic syndromes (MetS) and related cardiovascular diseases (CVDs) pose a serious threat to human health. MetS are metabolic disorders characterized by obesity, dyslipidemia, and hypertension, which increase the risk of CVDs' initiation and development. Although there are many availabile drugs for treating MetS and related CVDs, some side effects also occur. Considering the low-level side effects, many natural products have been tried to treat MetS and CVDs. A five-cyclic triterpenoid natural product, oleanolic acid (OA), has been reported to have many pharmacologic actions such as anti-hypertension, anti-hyperlipidemia, and liver protection. OA has specific advantages in the treatment of MetS and CVDs. OA achieves therapeutic effects through a variety of pathways, attracting great interest and playing a vital role in the treatment of MetS and CVDs. Consequently, in this article, we aim to review the pharmacological actions and potential mechanisms of OA in treating MetS and related CVDs.

Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain.

BACKGROUND: Depression is a recurrent and devastating mental disease that is highly prevalent worldwide. Prolonged exposure to stressful events or a stressful environment is detrimental to mental health. In recent years, an inflammatory hypothesis has been implicated in the pathogenesis of stress-induced depression. However, less attention has been given to the initial phases, when a series of stress reactions and immune responses are initiated. Peripheral CD4+ T cells have been reported as the major contributors to the occurrence of mental disorders. Chronic stress exposure-evoked release of cytokines can promote the differentiation of peripheral CD4+ cells into various phenotypes. Among them, Th17 cells have attracted much attention due to their high pathogenic potential in central nervous system (CNS) diseases. Thus, we intended to determine the crucial role of CD4+ Th17 cells in the development of specific subtypes of depression and unravel the underpinnings of their pathogenetic effect. METHODS: In the present research, a daily 6-h restraint stress paradigm was employed in rats for 28 successive days to mimic the repeated mild and predictable, but inevitable environmental stress in our daily lives. Then, depressive-like symptoms, brain-blood barrier (BBB) permeability, neuroinflammation, and the differentiation and functional changes of CD4+ cells were investigated. RESULTS: We noticed that restrained rats showed significant depressive-like symptoms, concomitant BBB disruption and neuroinflammation in the dorsal striatum (DS). We further observed a time-dependent increase in thymus- and spleen-derived naïve CD4+ T cells, as well as the aggregation of inflammatory Th17 cells in the DS during the period of chronic restraint stress (CRS) exposure. Moreover, increased Th17-derived cytokines in the brain can further impair the BBB integrity, thus allowing more immune cells and cytokines to gain easy access to the CNS. Our findings suggested that, through a complex cascade of events, peripheral immune responses were propagated to the CNS, and gradually exacerbated depressive-like symptoms. Furthermore, inhibiting the differentiation and function of CD4+ T cells with SR1001 in the early stages of CRS exposure ameliorated CRS-induced depressive-like behaviour and the inflammatory response. CONCLUSIONS: Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4+ T cells may be a promising therapeutic target for the early treatment of stress-induced depression.

Direct Interaction of Daxx and Androgen Receptor Is Required for Their Regulatory Activity in Cholesterol Biosynthesis.

INTRODUCTION: Homeostasis of cholesterol is crucial for cellular function, and dysregulated cholesterol biosynthesis is a metabolic event that can lead to hepatic and cardiovascular abnormalities. OBJECTIVE: The aim of this study was to investigate the effects and mechanisms of domain-associated protein (Daxx) and androgen receptor (AR) on intracellular cholesterol synthesis. METHODS: HepG2 cells were transfected with pCDNA3.1(+)/Daxx plasmid or treated with testosterone propionate to observe the effects of Daxx and AR on intracellular cholesterol levels. Co-immunoprecipitation experiments were performed to identify the interaction between Daxx and AR and to explore the regulatory effects of this interaction on cholesterol synthesis. RESULTS: Our experiments showed that AR promoted cholesterol synthesis and accumulation by activating sterol-regulatory element-binding protein isoform 2. AR-induced cholesterol synthesis was inhibited by Daxx; however, the expression of AR was not affected. Further studies demonstrated the existence of direct binding between Daxx and AR and this interaction was required to suppress AR activity. CONCLUSIONS: The Daxx-mediated antagonism of AR depicts a more complete picture as to how Daxx regulates intracellular cholesterol level and provides a new target for treatment of atherosclerosis.

PX Domain-Containing Kinesin KIF16B and Microtubule-Dependent Intracellular Movements.

As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.

Resolving neuroinflammation, the therapeutic potential of the anti-malaria drug family of artemisinin.

Artemisinin (Qinghaosu) and its semi-synthetic derivatives have been demonstrated to alleviate neuroinflammatory response in the central nerve system (CNS). In this review, we summarized that artemisinins are capable to treat neuroinflammtion-related CNS diseases in both direct (via regulating inflammatory process in the CNS, exerting anti-oxidative stress and neuroprotective effect, and preventing Aß accumulation) and indirect (via maintaining BBB integrity, suppressing systemic inflammation and alleviating intestinal inflammtion) manner. However, the precise mechanism of their anti-neuroinflammatory effects and potential neurotoxicity, which hindered further progress in these aspects, remains unclear. We suggest that further understanding of the PK/PD properties and structure-action relationship of atemisinin and its derivatives will facilitate the development of new therapeutics with better curative effects and safety.

Ablation of endothelial prolyl hydroxylase domain protein-2 promotes renal vascular remodelling and fibrosis in mice.

Accumulating evidence demonstrates that hypoxia-inducible factor (HIF-α) hydroxylase system has a critical role in vascular remodelling. Using an endothelial-specific prolyl hydroxylase domain protein-2 (PHD2) knockout (PHD2EC KO) mouse model, this study investigates the regulatory role of endothelial HIF-α hydroxylase system in the development of renal fibrosis. Knockout of PHD2 in EC up-regulated the expression of HIF-1α and HIF-2α, resulting in a significant decline of renal function as evidenced by elevated levels of serum creatinine. Deletion of PHD2 increased the expression of Notch3 and transforming growth factor (TGF-ß1) in EC, thus further causing glomerular arteriolar remodelling with an increased pericyte and pericyte coverage. This was accompanied by a significant elevation of renal resistive index (RI). Moreover, knockout of PHD2 in EC up-regulated the expression of fibroblast-specific protein-1 (FSP-1) and increased interstitial fibrosis in the kidney. These alterations were strongly associated with up-regulation of Notch3 and TGF-ß1. We concluded that the expression of PHD2 in endothelial cells plays a critical role in renal fibrosis and vascular remodelling in adult mice. Furthermore, these changes were strongly associated with up-regulation of Notch3/TGF-ß1 signalling and excessive pericyte coverage.

Curcumin enhances vascular contractility via induction of myocardin in mouse smooth muscle cells.

A variety of cardiovascular diseases is accompanied by the loss of vascular contractility. This study sought to investigate the effects of curcumin, a natural polyphenolic compound present in turmeric, on mouse vascular contractility and the underlying mechanisms. After mice were administered curcumin (100 mg·kg-1·d-1, ig) for 6 weeks, the contractile responses of the thoracic aorta to KCl and phenylephrine were significantly enhanced compared with the control group. Furthermore, the contractility of vascular smooth muscle (SM) was significantly enhanced after incubation in curcumin (25 µmol/L) for 4 days, which was accompanied by upregulated expression of SM marker contractile proteins SM22α and SM α-actin. In cultured vascular smooth muscle cells (VSMCs), curcumin (10, 25, 50 µmol/L) significantly increased the expression of myocardin, a "master regulator" of SM gene expression. Curcumin treatment also significantly increased the levels of caveolin-1 in VSMCs. We found that as a result of the upregulation of caveolin-1, curcumin blocked the activation of notch1 and thereby abolished Notch1-inhibited myocardin expression. Knockdown of caveolin-1 or activation of Notch1 signaling with Jagged1 (2 µg/mL) diminished these effects of curcumin in VSMCs. These findings suggest that curcumin induces the expression of myocardin in mouse smooth muscle cells via a variety of mechanisms, including caveolin-1-mediated inhibition of notch1 activation and Notch1-mediated repression of myocardin expression. This may represent a novel pathway, through which curcumin protects blood vessels via the beneficial regulation of SM contractility.

Identification of the C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol synthesis in HepG2 cells.

Daxx is a highly conserved nuclear transcriptional factor, which has been implicated in many nuclear processes including transcription and cell cycle regulation. Our previous study demonstrated Daxx also plays a role in regulation of intracellular cholesterol content. Daxx contains several domains that are essential for interaction with a growing number of proteins. To delineate the underlying mechanism of hypocholesterolemic activity of Daxx, we constructed a set of plasmids which can be used to overexpress different fragments of Daxx and transfected to HepG2 cells. We found that the C- terminal region Daxx626-740 clearly reduced intracellular cholesterol levels and inhibited the expression of SREBPs and SCAP. In GST pull-down experiments and Double immunofluorescence assays, Daxx626-740 was demonstrated to bind directly to androgen receptor (AR). Our findings suggest that the interaction of Daxx626-740 and AR abolishes the AR-mediated activation of SCAP/SREBPs pathway, which suppresses the de novo cholesterol synthesis. Thus, C-terminal domain of Daxx acts as a potential regulator of intracellular cholesterol content in HepG2 cells.

Polyacetylenic Oleanane-Type Triterpene Saponins from the Roots of Panax japonicus.

Three new polyacetylenic oleanane-type triterpenoids, baisanqisaponins A-C (1-3), and one new oleanane-type triterpenoid, chikusetsusaponin-V ethyl ester (4), together with 19 known compounds (5-23), were isolated from the roots of Panax japonicus. The structures were elucidated on the basis of spectroscopic analyses and chemical methods. Compounds 1-3 feature a rare panaxytriol group containing a polyacetylene on the saponin skeleton. Neuroprotective activity was evaluated for compounds 1-17, and angiotensin II-induced vascular smooth muscle cell proliferation inhibition was tested for compounds 5-7 and 10-12.

Subcellular localization of DAXX influence ox-LDL induced apoptosis in macrophages.

Here we aimed to evaluate the effects of DAXX subcellular localization on ox-LDL induced macrophages apoptosis. Cytoplasmic localization vector DAXX-W621A and nuclear localization vector DAXX-S667A were constructed by point mutation in DAXX. Blank vector, full length DAXX, DAXX-W621A, DAXX-S667A was transfect into RAW264.7 cells, respectively. Then the cells were incubated with 100 mg/ml ox-LDL for 48 h. Immunofluorescent assay was used to assay the localization of DAXX. MTT and Flow cytometry was used to determine cellular viability and apoptosis. RT-PCR and Western blot were used to analyze the expression levels. A significantly increased expression of DAXX was found in transfected cells of DAXX. The content of DAXX in nucleus was significantly increased in DAXX(S667A), and DAXX was significantly increased in cytoplasm of DAXX(W621A). Besides, we found DAXX was mainly expressed in nucleus with a low-level expression in cytoplasm through immunofluorescence. However in DAXX(W621A) group, the DAXX began to transferred to cytoplasm, which exhibited significant florescence. After treated with ox-LDL, the cytoactive of DAXX-W621A exhibited significantly decreased level when compared DAXX group. However, after added inhibitor LMB, the inhibition was relieved. The cell viability was also significantly increased in DAXX-S667A group. The results of apoptosis rates were similar in each group. Furthermore, we found the expression of ASK1 and JNK was also consistent with the apoptosis rates. Cytoplasmic localization of DAXX can increase injury sensitivity of ox-LDL on cells, and nuclear localization can antagonise the effect of ox-LDL. Besides, it is certified ox-LDL induced apoptosis is mainly through ASK1-JNK pathway.

Ezetimibe-mediated protection of vascular smooth muscle cells from cholesterol accumulation through the regulation of lipid metabolism-related gene expression.

BACKGROUND: Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efflux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions. METHODS AND RESULTS: Rat VSMCs were converted to foam cells by incubation with cholesterol:methyl-ß-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 µmol/l) or treated with 30 µmol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor α, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin-1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1. CONCLUSION: The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes.

The Regulatory Role and Mechanism of Energy Metabolism in Vascular Diseases.

Vascular diseases are amongst the most serious diseases affecting human life and health globally. Energy metabolism plays a crucial role in multiple vascular diseases, and the imbalance of energy metabolism in cells from the blood vessel wall can cause various vascular diseases. Energy metabolism studies have often focused on atherosclerosis (AS) and pulmonary hypertension (PH). However, the roles of energy metabolism in the development of other vascular diseases is becoming increasingly appreciated as both dynamic and essential. This review summarizes the role of energy metabolism in various vascular diseases, including AS, hemangioma, aortic dissection, PH, vascular aging, and arterial embolism. It also discusses how energy metabolism participates in the pathophysiological processes of vascular diseases and potential drugs that may interfere with energy metabolism. This review presents suggestions for the clinical prevention and treatment of vascular diseases from the perspective of energy metabolism.

Dipsacoside B ameliorates cognitive impairment in sepsis-associated encephalopathy by reducing Th17 cell infiltration and neuroinflammation.

Sepsis-associated encephalopathy (SAE) is the main cause of cognitive impairment in patients with sepsis. The infiltration of inflammatory signals into the central nervous system (CNS) via the compromised blood-brain barrier (BBB) represents a crucial step in the pathological progression of SAE. In particular, T-helper 17 cell (Th17 cells) has been suggested to be highly correlated with the activation of central immune responses. Thus, preventing Th17 cell infiltration into the CNS may be a possible strategy to alleviate cognitive decline in SAE. Dipsacoside B (DB) is one of the primary active components in Chuan Xu Duan (Dipsacus asper Wall). We speculate that DB may be a potential candidate for the treatment of SAE-related cognitive deficits. In the present study, we demonstrated that DB could effectively alleviate cognitive impairment in SAE mice. DB significantly suppressed the central inflammatory response induced by repeated lipopolysaccharide (LPS) injection. The mechanism underlying its therapeutic effect should be attributed to the reduction of BBB impairment and pathogenic Th17 cell infiltration into the CNS by inhibition of vascular endothelial growth factor A (VEGFA)/ Vascular endothelial growth factor receptor 2(VEGFR2)/ Endothelial nitric oxide synthase (eNOS) signaling. Our findings suggest that DB is a potential candidate for the treatment of SAE-related cognitive dysfunction.

Curcumin nicotinate increases LDL cholesterol uptake in hepatocytes through IDOL/LDL-R pathway regulation.

BACKGROUND: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid-lowering effects. OBJECTIVE: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes. METHODS: Differential metabolites in Curtn-treated HepG2 cells were identified via LC-MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high-fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes. RESULTS: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors. CONCLUSION: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy.

[Effects of SUMOylation on the subcellular localization and function of DAXX].

Death domain-associated protein (DAXX) as a multifunctional nuclear protein widely resides in nucleolus, nucleoplasm, chromatin, promyelocytic leukaemia nuclear bodies (PML-NBs) and cytoplasm. It plays significant roles in transcriptional regulation, apoptosis, cell cycle and other biological activities. Small ubiquitin-like modifier (SUMO) is required for SUMOylation which is a highly conserved post-translational modification in a wide variety of cellular processes. Numerous studies demonstrated that SUMOylation has a great effect on the subcellular localization and functional regulation of DAXX. This review will provide a summary for SUMOylation of DAXX.

The role of lncRNA-mediated pyroptosis in cardiovascular diseases.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Pyroptosis is a unique kind of programmed cell death that varies from apoptosis and necrosis morphologically, mechanistically, and pathophysiologically. Long non-coding RNAs (LncRNAs) are thought to be promising biomarkers and therapeutic targets for the diagnosis and treatment of a variety of diseases, including cardiovascular disease. Recent research has demonstrated that lncRNA-mediated pyroptosis has significance in CVD and that pyroptosis-related lncRNAs may be potential targets for the prevention and treatment of specific CVDs such as diabetic cardiomyopathy (DCM), atherosclerosis (AS), and myocardial infarction (MI). In this paper, we collected previous research on lncRNA-mediated pyroptosis and investigated its pathophysiological significance in several cardiovascular illnesses. Interestingly, certain cardiovascular disease models and therapeutic medications are also under the control of lncRNa-mediated pyroptosis regulation, which may aid in the identification of new diagnostic and therapy targets. The discovery of pyroptosis-related lncRNAs is critical for understanding the etiology of CVD and may lead to novel targets and strategies for prevention and therapy.

Dipsacoside B Inhibits the Migration and Proliferation of VSMCs and Blunts Neointimal Formation by Upregulating PTEN Expression.

BACKGROUND: To investigate the effect and potential molecular mechanisms of Dipsacoside B (DB), an herb monomer extracted from Dipsacusasper or Lonicera macranthoides, on the migration and proliferation of vascular smooth muscle cells (VSMCs) and balloon-induced neointimal formation. METHODS: In vivo, rat abdominal aorta balloon injury model was utilized to investigate the effect of DB on the neointimal formation. In vitro, cultured VSMCs were used to investigate the effect of DB on Angiotensin-II (Ang-II)-induced migration and proliferation of VSMCs. Western blot and immunofluorescence were used to measure PTEN expression. RESULTS: As compared to vehicle control balloon-injury group, DB treatment significantly inhibited the neointimal formation together up-regulated the expression of phosphatase and tension homolog deleted on chromosome 10 (PTEN). Cell proliferations (MTT and Edu incorporation) assays and wound migration measurement further revealed that treatment with DB significantly blunted Ang-II-induced proliferation and migration potential of VSMCs. Western blot analysis exhibited that DB upregulated the expression of PTEN in vivo and in vitro. CONCLUSIONS: DB treatment suppresses the proliferation and migration of VSMCs and reduces neointimal formation by the mechanisms involving regulating the phenotype switch of VSMCs via upregulating PTEN expression.

Network Pharmacology-Based Strategy Combined with Molecular Docking and in vitro Validation Study to Explore the Underlying Mechanism of Huo Luo Xiao Ling Dan in Treating Atherosclerosis.

Background: Huo Luo Xiao Ling Dan (HLXLD), a famous Traditional Chinese Medicine (TCM) classical formula, possesses anti-atherosclerosis (AS) activity. However, the underlying molecular mechanisms remain obscure. Aim: The network pharmacology approach, molecular docking strategy, and in vitro validation experiment were performed to explore the potential active compounds, key targets, main signaling pathways, and underlying molecular mechanisms of HLXLD in treating AS. Methods: Several public databases were used to search for active components and targets of HLXLD, as well as AS-related targets. Crucial bioactive ingredients, potential targets, and signaling pathways were acquired through bioinformatics analysis. Subsequently, the molecular docking strategy and molecular dynamics simulation were carried out to predict the affinity and stability of active compounds and key targets. In vitro cell experiment was performed to verify the findings from bioinformatics analysis. Results: A total of 108 candidate compounds and 321 predicted target genes were screened. Bioinformatics analysis suggested that quercetin, dihydrotanshinone I, pelargonidin, luteolin, guggulsterone, and ß-sitosterol may be the main ingredients. STAT3, HSP90AA1, TP53, and AKT1 could be the key targets. MAPK signaling pathway might play an important role in HLXLD against AS. Molecular docking and molecular dynamics simulation results suggested that the active compounds bound well and stably to their targets. Cell experiments showed that the intracellular accumulation of lipid and increased secretory of TNF-α, IL-1ß, and MCP-1 in ox-LDL treated RAW264.7 cells, which can be significantly suppressed by pretreating with dihydrotanshinone I. The up-regulation of STAT3, ERK, JNK, and p38 phosphorylation induced by ox-LDL can be inhibited by pretreating with dihydrotanshinone I. Conclusion: Our findings comprehensively demonstrated the active compounds, key targets, main signaling pathways, and underlying molecular mechanisms of HLXLD in treating AS. These findings would provide a scientific basis for the study of the complex mechanisms underlying disease and drug action.

Curcumin nicotinate decreases serum LDL cholesterol through LDL receptor-mediated mechanism.

Curcumin nicotinate (Curtn) is a synthesized ester derivative of curcumin and niacin. Our previous study has shown that Curtn lowers serum low-density lipoprotein cholesterol (LDL-C) levels in apoE-/- mice and promotes LDL-C uptake into HepG2 cells in vitro. The present study was to test the hypothesis that Curtn decreases serum LDL-C levels through decreased expression of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and subsequent increase in LDL receptor expression. Male Wistar rats on high-fat diet (HFD) were treated with Curtn or rosuvastatin. Curtn or rosuvastatin treatment significantly decreased serum levels of total cholesterol (TC) and LDL-C in rats on HFD with increased liver LDL receptor expression. LDL-C-lowering effect of Curtn was not observed in LDL receptor deficient (LDLR-/-) mice on HFD, while rosuvastatin still decreased serum lipid levels in LDLR-/- mice, indicating that the reduction of serum LDL-C levels by Curtn treatment was LDL receptor-dependent. Curtn treatment also significantly decreased the protein expression of PCSK9 in Wistar rats and LDLR-/- mice. In HepG2 cells with overexpression of human PCSK9, Curtn treatment significantly increased LDL-C uptakes into hepatocytes, and increased LDL receptor distribution on cell surface in association with decreased PCSK9 protein expression. RNAi-LDLR significantly attenuated the effect of Curtn on LDLR distribution on cell surface. These data indicates that Curtn would decrease serum LDL-C level at least partially through inhibition of PCSK9 expression, and subsequent increase in LDL receptor expression and distribution in hepatocytes, serving as a potential novel compound to treat hyperlipidemia.

Angiopoietin-1 protects myocardial endothelial cell function blunted by angiopoietin-2 and high glucose condition.

AIM: To evaluate the effects of angiopoietin-1 (Ang-1) on myocardial endothelial cell function under high glucose (HG) condition. METHODS: Mouse heart myocardial endothelial cells (MHMECs) were cultured and incubated under HG (25 mmol/L) or normal glucose (NG, 5 mmol/L) conditions for 72 h. MTT was used to determine cellular viability, and TUNEL assay and caspase-3 enzyme linked immunosorbent assays were used to assay endothelial apoptosis induced by serum starvation. Immunoprecipitation and Western blot analysis were used to analyze protein phosphorylation and expression. Endothelial tube formation was used as an in vitro assay for angiogenesis. RESULTS: Exposure of MHMECs to HG resulted in dramatic decreases in phosphorylation of the Tie-2 receptor and its downstream signaling partners, Akt/eNOS, compared to that under NG conditions. Ang-1 (250 ng/mL) increased Tie-2 activation, inhibited cell apoptosis, and promoted angiogenesis. Ang-1-mediated protection of endothelial function was blunted by Ang-2 (25 ng/mL). CONCLUSION: Ang-1 activates the Tie-2 pathway and restores hyperglycemia-induced myocardial microvascular endothelial dysfunction. This suggests a protective role of Ang-1 in the ischemic myocardium, particularly in hearts affected by hyperglycemia or diabetes.