Association of Body Surface Area Versus Body Mass Index on Outcomes in Peripheral Arterial Disease.

OBJECTIVE: Numerous studies have indicated that increased obesity in patients with established peripheral artery disease (PAD) is inversely associated with disease prognosis, a phenomenon coined as the "obesity paradox". A major cause of criticism in studies investigating the obesity paradox is the use of body mass index (BMI) as a surrogate marker in defining and quantifying the degree or severity of obesity. We conducted a retrospective review to verify whether the obesity paradox persists in patients with PAD when using body surface area (BSA) as an alternative anthropometric measure. METHODS: Patients undergoing surgery (open or endovascular) for PAD between January 2009 and March 2020 were identified from the Vascular Quality Initiative (VQI) national database. The association between BSA/BMI and risk of post-operative complications was evaluated using logistic regression and restricted cubic spline analysis, both of which adjusted for demographic and comorbid risk predictors. When analyzing BSA and BMI as categorical variables, patients were grouped according to BSA quintiles and the World Health Organization (WHO) BMI categories. RESULTS: A total of 130,428 patients were included based on our eligibility criteria, of which 85,394 (65.5%) were men. Patients were typically hypertensive (87.8%), diabetic (50.4%), and overweight (63.0% over 25 kg/m2). Patients with a high BMI or BSA typically presented at a younger age and with greater pre-operative administration of drugs (statin, ACE-inhibitor, anticoagulant, and beta blocker). Our results indicate that BSA and BMI are inversely associated with post-operative risk of all-cause morbidity, mortality, and cardiac complications. This finding was displayed when analyzing BMI/BSA as a continuous variable, or when indexing patients into BMI/BSA groups. CONCLUSION: Our data suggests that the obesity paradox persists in patients with PAD when using either BMI or BSA as anthropometric measures. Future studies with a prospective design and utilizing newer anthropometric indices should be conducted to fully verify the presence of this phenomenon.

Cardio-oncology in China.

OPINION STATEMENT: Cardio-oncology is going under rapid development in various areas across an increasing number of provinces in China. However there are still a myriad of challenges that need to be overcome in order to ensure its gradual and consistent expansion. The Cardio-Oncology Knowledge Transfer Model (KTM) forms the basis to allow exponential development of effective cardio-oncology services. This would ensure the implementation of precision-based practice while dynamically evolving cardio-oncology to integrate both Western and Chinese medical practices to become an official clinical sub-speciality in its own right in China, for the ultimate benefit of the patient.

Novel Three-Dimensional Printed Human Heart Models and Ultrasound Omniplane Simulator for Transesophageal Echocardiography Training.

Simulation-based training plays an essential role in transesophageal echocardiography (TEE) education. Using 3-dimensional printing technology, the authors invented a novel TEE teaching system consisting of a series of heart models that can be segmented according to actual TEE views, and an ultrasound omniplane simulator to demonstrate how ultrasound beams intersect the heart at different angles and generate images. This novel teaching system is able to provide a more direct way to visualize the mechanics of obtaining TEE images than traditional online or mannequin-based simulators. It can also provide tangible feedback of both an ultrasound scan plane and a TEE view of the heart, which has been proven to improve trainees' spatial awareness and can significantly help in understanding and memorizing complex anatomic structures. This teaching system itself is also portable and inexpensive, making it conducive to teaching TEE in regions of diverse economic status. This teaching system also can be expected to be used for just-in-time training in a variety of clinical scenarios, including operating rooms, intensive care units, etc.

Androgen increases klotho expression via the androgen receptor-mediated pathway to induce GCs apoptosis.

BACKGROUND: Many epidemiological studies have shown that anovulatory polycystic ovary syndrome (PCOS) is accompanied by hyperandrogenism. However, the exact mechanism of hyperandrogen-induced anovulation remains to be elucidated. In this study, we aimed to investigate the potential mechanism of anovulation in PCOS. To investigate the role of klotho as a key factor in the androgen receptor (AR)-mediated development of PCOS, we investigated the effects of testosterone on ovarian klotho expression in vivo and in vitro. RESULTS: Testosterone propionate (TP)-induced rats showed cycle irregularity, hyperandrogenism, polycystic ovarian changes, dyslipidemia. However, inhibition of AR expression could relieve PCOS traits. We also found that AR and klotho showed relatively high expression in PCOS rat ovarian tissue and in TP-induced granulosa cells (GCs), which was inhibited by the addition of flutamide. TP-induced GCs apoptosis was suppressed by AR antagonist, as well as silencing klotho expression in human GCs. Chromatin immunoprecipitation assay demonstrated that AR indirectly binds to the klotho promoter. CONCLUSIONS: Our results demonstrated TP mediates the expression of klotho via androgen receptor and klotho alterations could be a reason for ovarian dysfunction in PCOS.

4­Methoxydalbergione inhibits esophageal carcinoma cell proliferation and migration by inactivating NF­κB.

4­Methoxydalbergione (4­MD) can inhibit the progression of certain types of cancer; however, its effects on esophageal cancer (EC) remain unclear. The present study aimed to investigate the inhibitory effect of 4­MD on EC and its molecular mechanism. ECA­109 and KYSE­105 cells were treated with or without lipopolysaccharide (LPS) and 4­MD. Cell Counting Kit­8 and colony formation assays were used to analyze cell proliferation. Wound healing assay was performed to evaluate cell migration. ELISA and western blotting were performed to measure the expression levels of NF­κB and inflammatory cytokines. In cells treated with 4­MD, proliferation and migration were significantly inhibited, the levels of inflammatory cytokines were downregulated and the NF­κB signaling pathway was inactivated. Notably, proliferation, migration, inflammation and NF­κB were promoted by LPS, whereas 4­MD reversed the increases induced by LPS in EC cells. In conclusion, 4­MD may attenuate the proliferation and migration of EC cells by inactivating the NF­κB signaling pathway.

Role of Neurite Outgrowth Inhibitor B Receptor in hepatic steatosis.

Hepatic steatosis, characterized by excessive lipid accumulation, is one of the common liver diseases. Neurite Outgrowth Inhibitor B Receptor (NgBR) regulates the lipid metabolism, cholesterol efflux, and protein glycosylation. Recently, it has been demonstrated that NgBR deficiency leads to hepatic steatosis. In this review we summarize the current knowledge about the structure of NgBR, the role and molecular mechanism of NgBR in the occurrence and development of hepatic steatosis.

Application of metagenomic next-generation sequencing for suspected infected pancreatic necrosis.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) is increasingly used for the clinical diagnosis of infectious diseases, but there is a paucity of data regarding the application of mNGS in the early diagnosis of infected pancreatic necrosis (IPN). OBJECTIVE: To investigate the clinical application value of mNGS in the pathogenic diagnosis of IPN. METHODS: Forty-two patients with suspected IPN were prospectively and consecutively enrolled from August 2019 to August 2021. Blood samples were collected for mNGS and microbial culture simultaneously during fever (T ≥ 38.5 °C). For patients who had indications of surgical interventions, peri-pancreatic specimens were collected for mNGS and microbial culture simultaneously during the first surgical intervention to confirm IPN. The clinical performance of mNGS and microbial culture were compared. RESULTS: A total of 21 patients (50.0%) were confirmed to have IPN during hospitalization. The sensitivity of blood mNGS was significantly higher than blood culture (95.2% vs. 23.8%, P < 0.001) in diagnosing IPN. The negative predictive value of blood mNGS was 90.0%. The turnaround time of mNGS was significantly shorter than that of microbial culture [(37.70 ± 1.44) vs. (115.23 ± 8.79) h, P < 0.01] and the average costs of mNGS accounted for 1.7% of the average total cost of hospitalization. The survival analysis demonstrates that the positive blood mNGS result was not associated with increased mortality (P = 0.119). CONCLUSIONS: With more valuable diagnostic performance and shorter turnaround time, clinical mNGS represents a potential step forward in the early diagnosis of IPN.

Multiple pathophysiological roles of midkine in human disease.

Midkine (MK) is a low molecular-weight protein that was first identified as the product of a retinoic acid-responsive gene involved in embryonic development. Recent studies have indicated that MK levels are related to various diseases, including cardiovascular disease (CVD), renal disease and autoimmune disease. MK is a growth factor involved in multiple pathophysiological processes, such as inflammation, the repair of damaged tissues and cancer. The pathophysiological roles of MK are diverse. MK enhances the recruitment and migration of inflammatory cells upon inflammation directly and also through induction of chemokines, and contributes to tissue damage. In lung endothelial cells, oxidative stress increased the expression of MK, which induced angiotensin-converting enzyme (ACE) expression and the consequent conversion from Ang I to Ang II, leading to further oxidative stress. MK inhibited cholesterol efflux from macrophages by reducing ATP-binding cassette transporter A1 (ABCA1) expression, which is involved in lipid metabolism, suggesting that MK is an important positive factor involved in inflammation, oxidative stress and lipid metabolism. Furthermore, MK can regulate the expansion, differentiation and activation of T cells as well as B-cell survival; mediate angiogenic and antibacterial activity; and possess anti-apoptotic activity. In this paper, we summarize the pathophysiological roles of MK in human disease.

Mitochondrial Dysfunction in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common female reproductive metabolisms. It is an endocrine disease that affects reproductive women and often exhibits with hyperandrogenemia, insulin resistance (IR), low inflammation, and an increased risk of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular events such as hypertension and dyslipidemia in patients. However, the molecular mechanism of PCOS is still unclear. Recently, an increasing number of studies have shown that the oxidative stress induced by mitochondrial dysfunction has negative effects on IR, lipid metabolism, and follicular development, suggesting that mitochondrial dysfunction plays an essential role in the development of PCOS. Abnormal mitochondrial DNA copy number in patients with PCOS, and mitochondrial gene mutations, has been the focus of research in recent years, and functional mitochondrial diseases have been gradually accepted as a related factor in PCOS. This review is intended to summarize and discuss previous and recent studies and findings on the connections between mitochondrial dysfunction and PCOS.

Digoxin is associated with worse outcomes in patients with heart failure with reduced ejection fraction.

AIMS: The aim of this study was to investigate the impact of digoxin use on the outcomes of patients with heart failure with reduced ejection fraction (HFrEF) and its possible interaction with atrial fibrillation or use of currently guideline-recommended treatments in the real world in China. METHODS AND RESULTS: Patients hospitalized with HFrEF from 45 hospitals participating in the China National Heart Failure Registration Study (CN-HF) were enrolled to assess the all-cause mortality, HF mortality, all-cause re-hospitalization, and HF re-hospitalization associated with digoxin use. Eight hundred eighty-two eligible HFrEF patients in the CN-HF registry were included: 372 patients with digoxin and 510 patients without digoxin. Among them, 794 (90.0%) patients were followed up for the endpoint events, with a median follow-up of 28.6 months. Kaplan-Meier survival analysis showed that the all-cause mortality (P < 0.001) and all-cause re-hospitalization (P = 0.020) were significantly higher in digoxin group than non-digoxin group, while HF mortality (P = 0.232) and HF re-hospitalization (P = 0.098) were similar between the two groups. The adjusted Cox proportional-hazards regression analysis demonstrated that digoxin use remained as an independent risk factor for increased all-cause mortality [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.27-2.44; P = 0.001] and all-cause re-hospitalization (HR 1.27; 95% CI 1.03-1.57; P = 0.029) in HFrEF patients and the predictive value of digoxin for all-cause mortality irrespective of rhythm or in combination with other guideline-recommended therapies. CONCLUSIONS: Digoxin use is independently associated with increased risk of all-cause mortality and all-cause re-hospitalization in HFrEF patients.

Improved therapeutic effects on diabetic foot by human mesenchymal stem cells expressing MALAT1 as a sponge for microRNA-205-5p.

Diabetic foot (DF) is a common complication of high severity for diabetes, a prevalent metabolic disorder that affects billions of people worldwide. Mesenchymal stem cells (MSCs) have a demonstrative therapeutic effect on DF, through their generation of pro-angiogenesis factors, like vascular endothelial growth factor (VEGF). Recently, genetically modified MSCs have been used in therapy and we have shown that depletion of micoRNA-205-5p (miR-205-5p) in human MSCs promotes VEGF-mediated therapeutic effects on DF. Here, we showed that a long non-coding RNA (lncRNA), MALAT1, is a competing endogenous RNA (ceRNA) for miR-205-5p, and is low expressed in human MSCs. Ectopic expression of MALAT1 in human MSCs significantly decreased miR-205-5p levels, resulting in upregulation of VEGF production and improved in vitro endothelial cell tube formation. In a DF model in immunodeficient NOD/SCID mice, transplantation of human miR-205-5p-depleted MSCs exhibited better therapeutic effects on DF recovery than control MSCs. Moreover, MALAT1-expressing MSCs showed even better therapeutic effects on DF recovery than miR-205-5p-depleted MSCs. This difference in DF recovery was shown to be associated with the levels of on-site vascularization. Together, our data suggest that MALAT1 functions as a sponge RNA for miR-205-5p to increase therapeutic effects of MSCs on DF.

Outcomes of patients with anemia and renal dysfunction in hospitalized heart failure with preserved ejection fraction (from the CN-HF registry).

BACKGROUND: Although a large number of studies on heart failure with reduced ejection fraction (HFrEF) have found that anemia and renal dysfunction (RD) independently predicted poor outcomes, there are still few reports on patients with heart failure with preserved ejection fraction (HFpEF). METHODS: Clinical data of HFpEF patients registered in the China National Heart Failure Registration Study (CN-HF) were evaluated and the clinical features of patients with or without anemia/RD were compared to explore the impact of anemia and RD on all-cause mortality and all-cause re-hospitalization. RESULTS: 1604 patients with HFpEF were enrolled, the prevalence of anemia was 51.0%. Although anemia was associated with increased risk of all-cause mortality and all-cause re-hospitalization in univariate COX regression (p < 0.05), multivariate COX model confirmed that anemia was not independently associated with all-cause mortality [hazard ratio (HR) 1.14, 95% confidence interval (CI) 0.85-1.52, p = 0.386] and all-cause re-hospitalization (HR 1.13, 95% CI 0.96-1.33, p = 0.152). Similarly, RD was not an independent predictor of all-cause mortality (HR 1.18, 95% CI 0.88-1.57, p = 0.269) and all-cause re-hospitalization (HR 0.94, 95% CI 0.79-1.12, p = 0.488) as assessed in the adjusted COX regression model. The interaction between RD and anemia on end-points events was also not statistically significant. However, anemia was associated with increased all-cause re-hospitalization in patients with New York Heart Association (NYHA) class III-IV. CONCLUSIONS: In patients with HFpEF from CN-HF registry, anemia was common, but was not an independent predictor of all-cause mortality and all-cause re-hospitalization, except for the all-cause re-hospitalization in patients with NYHA class III-IV.Clinical Trial Registration: http://www.clinicaltrials.gov/ct2/home; ID: NCT02079428.

Cilostazol ameliorates high free fatty acid (FFA)-induced activation of NLRP3 inflammasome in human vascular endothelial cells.

Cardiovascular disease is recognized as a leading cause of death worldwide, but the risk of death is 2-3 times higher for individuals with diabetes. NLRP3 inflammasome activation is a leading pathway of vascular damage, and new treatment methods are needed to reduce NLRP3 inflammasome expression, along with a detailed understanding of how those treatments work. In a series of assays on human vascular endothelial cells that were exposed to high concentrations of free fatty acids (FFA) to induce a diabetes-like environment, we found a significant impact of cilostazol, a vasodilator widely used to treat blood flow problems and well-tolerated medication. To our knowledge, this study is the first to demonstrate the effects of cilostazol in primary human aortic endothelial cells. We found that cilostazol significantly reduced NLRP3 inflammasome activation, as well as the activity of other related and harmful factors, including oxidative stress, expression of NADPH oxidase 4 (NOX-4), thioredoxin-interacting protein (TxNIP), high mobility group box 1 (HMGB-1), interleukin 1ß (IL-1ß) and IL-18. Cilostazol also protected the functionality of sirtuin 1 (SIRT1), which serves to restrict NLRP3 inflammasome activity, when exposure to FFAs would have otherwise impaired its function. Thus, it appears that cilostazol's mechanism of action in reducing NLRP3 inflammasome activation is an indirect one; it protects SIRT1, which then allows SIRT1 to perform its regulatory job. Cilostazol has potential as an already-available, well-tolerated preventive medication that may alleviate some of the adverse vascular effects of living with diabetes. The findings of the present study lay the groundwork for further research on the potential of cilostazol as a safe and effective treatment against diabetic endothelial dysfunction and vacular disease.

MicroRNA-21 suppresses ox-LDL-induced human aortic endothelial cells injuries in atherosclerosis through enhancement of autophagic flux: Involvement in promotion of lysosomal function.

Atherosclerosis is a common pathological basis of cardiovascular disease and remains the leading cause of mortality. Endothelial cell (EC) injury and autophagy dysfunction have been proved to contribute to the development of atherosclerosis. Recently, accumulating evidence confirms that microRNAs (miRNAs) have emerged as vital regulators and fine-tuners of various pathophysiological cellular impacts and molecular signaling pathways involved in atherosclerosis. Herein, the objective of the present study was to explore the biological function of miR-21 in oxidized low-density lipoprotein (ox-LDL)-induced human aortic endothelial cells (HAECs) injury and the underlying molecular mechanism. The results showed that ox-LDL treatment significantly decreased HAECs viability, increased caspase-3 activity, apoptosis ratio and Bax protein expression, and reduced Bcl-2 protein expression resulting in EC injuries. Simultaneously, ox-LDL treatment obviously reduced miR-21 level in a time-and dose-dependent manner. Notably, ox-LDL-induced EC injuries were abolished by miR-21 mimics transfection. In addition, miR-21 mimics alleviated ox-LDL-induced impaired autophagic flux as illustrated by the increases in LC3-II/LC3-I ratio and Beclin-1 protein expression, and the decrease in p62 protein expression in HAECs. Moreover, ox-LDL suppressed the expressions of lysosomal membrane protein (LAMP1) and cathepsin D proteins, and attenuated cathepsin D activity in HAECs, leading to lysosomal dysfunction, while these effects were also blocked by miR-21 mimics. These findings indicated that miR-21 restored impaired autophagic flux and lysosomal dysfunction, thereby attenuating ox-LDL-induced HAECs injuries.

Secretory leukocyte protease inhibitor promising protective roles in obesity-associated atherosclerosis.

Secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor, which was most commonly examined in mucosal fluids such as saliva, is a versatile molecule and plays non-redundant roles. In addition to its anti-protease activity, SLPI has been shown to express anti-bacterial, anti-viral, anti-fungal, and anti-inflammatory properties as well as participating in innate and adaptive immune responses, most of which has been well documented. Recently, it is reported that SLPI is expressed in adipocytes and adipose tissue where it could play an important feedback role in the resolution of inflammation. Furthermore, circulating SLPI has been shown to correlate with progressive metabolic dysfunction. Moreover, adenoviral gene delivery of elafin and SLPI attenuates nuclear factor-κB-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. This review contributes to unraveling the protective role of SLPI in obesity-related atherosclerosis development, and the potential role in preventing arterial plaque rupture.

L-4F Inhibits Oxidized Low-density Lipoprotein-induced Inflammatory Adipokine Secretion via Cyclic AMP/Protein Kinase A-CCAAT/Enhancer Binding Protein ß Signaling Pathway in 3T3-L1 Adipocytes.

BACKGROUND: Adipocytes behave like a rich source of pro-inflammatory cytokines including monocyte chemoattractant protein-1 (MCP-1). Oxidized low-density lipoprotein (oxLDL) participates in the local chronic inflammatory response, and high-density lipoprotein could counterbalance the proinflammatory function of oxLDL, but the underlying mechanism is not completely understood. This study aimed to evaluate the effect of apolipoprotein A-I mimetic peptide L-4F on the secretion and expression of MCP-1 in fully differentiated 3T3-L1 adipocytes induced by oxLDL and to elucidate the possible mechanisms. METHODS: Fully differentiated 3T3-L1 adipocytes were incubated in the medium containing various concentration of L-4F (0-50 µg/ml) with oxLDL (50 µg/ml) stimulated, with/without protein kinase A (PKA) inhibitor H-89 (10 µmol/L) preincubated. The concentrations of MCP-1 in the supernatant, the mRNA expression of MCP-1, the levels of CCAAT/enhancer binding protein α (C/EBPα), and CCAAT/enhancer binding protein ß (C/EBPß) were evaluated. The monocyte chemotaxis assay was performed by micropore filter method using a modified Boyden chamber. RESULTS: OxLDL stimulation induced a significant increase of MCP-1 expression and secretion in 3T3-L1 adipocytes, which were inhibited by L-4F preincubation in a dose-dependent manner. PKA inhibitor H-89 markedly reduced the oxLDL-induced MCP-1 expression, but no further decrease was observed when H-89 was used in combination with L-4F (50 µg/ml) (P > 0.05). OxLDL stimulation showed no significant effect on C/EBPα protein level but increased C/EBPß protein level in a time-dependent manner. H-89 and L-4F both attenuated C/EBPß protein level in oxLDL-induced 3T3-L1 adipocytes. CONCLUSIONS: OxLDL induces C/EBPß protein synthesis in a time-dependent manner and enhances MCP-1 secretion and expression in 3T3-L1 adipocytes. L-4F dose-dependently counterbalances the pro-inflammatory effect of oxLDL, and cyclic AMP/PKA-C/EBPß signaling pathway may participate in it.

The role of autophagy in cardiac hypertrophy.

Autophagy is conserved in nature from lower eukaryotes to mammals and is an important self-cannibalizing, degradative process that contributes to the elimination of superfluous materials. Cardiac hypertrophy is primarily characterized by excess protein synthesis, increased cardiomyocyte size, and thickened ventricular walls and is a major risk factor that promotes arrhythmia and heart failure. In recent years, cardiomyocyte autophagy has been considered to play a role in controlling the hypertrophic response. However, the beneficial or aggravating role of cardiomyocyte autophagy in cardiac hypertrophy remains controversial. The exact mechanism of cardiomyocyte autophagy in cardiac hypertrophy requires further study. In this review, we summarize the controversies associated with autophagy in cardiac hypertrophy and provide insights into the role of autophagy in the development of cardiac hypertrophy. We conclude that future studies should emphasize the relationship between autophagy and the different stages of cardiac hypertrophy, as well as the autophagic flux and selective autophagy. Autophagy will be a potential therapeutic target for cardiac hypertrophy.

IL-8 up-regulates proliferative angiogenesis in ischemic myocardium in rabbits through phosphorylation of Akt/GSK-3ß(ser9) dependent pathways.

BACKGROUND: Therapeutic myocardial angiogenesis is an important compensatory mechanism in severely coronary stenosis. Previous studies demonstrated that interleukin-8 (IL-8) not only plays an important role in inflammation, but also a potent angiogenic factor through p38 mitogen-activated protein kinase (p38MAPK), nuclear factor-kappaB (NK-κB)-dependent pathway in carcinoma. Our study sought to investigate the effects of IL-8 on the angiogenesis and the underlying mechanism in the ischemic myocardium. METHODS: Acute myocardial infarction animal model was established with male rabbits by directly suturing the left anterior descending branch, then lentivirus-mediated IL-8 was quarterly injected into the borderline of infarction area immediately. We employed CoCl2 induced hypoxic HUVECs for in vitro ischemia study. Left ventricular end-diastolic diameter (LVEDd) and ejection fraction (EF) were measured by echocardiography in pre-operation and at 6(th) week after operation. CD34 was detected with immunohistochemisty to analyse angiogenesis. Western blot was performed with regard to IL-8, protein kinase B (PKB/Akt) and Glycogen synthase kinase-3ß(ser9) (GSK-3ß(ser9)). For the HUVECs' proliferation and apoptosis, multiscan spectrum reader at A570 nm and annexin V-FITC/PI staining method were used respectively. RESULTS: The levels of IL-8, phosphorylated Akt and GSK-3ß(ser9) in focal myocardium significantly increased, and the over expression of IL-8 led to an increasing in angiogenesis in rabbits. Hypoxia inhibited cell proliferation and promoted apoptosis. IL-8 induced cell proliferation, phosphorylation of Akt and GSK-3ß(ser9), inhibited apoptosis and Caspase3 expression in HUVECs, which were attenuated by anti-IL-8 or the Akt inhibitor LY294002. CONCLUSIONS: The present results indicate that IL-8 can increase angiogenesis in myocardial infarction, which maybe through enhancing Akt and GSK-3ß(ser9) expression, and inhibiting myocardial apoptosis.

High-density lipoprotein increases the uptake of oxidized low density lipoprotein via PPARγ/CD36 pathway in inflammatory adipocytes.

AIM: Previous studies have demonstrated that the dysregulated-secretion of adipokines by adipocytes may contribute to obesity-associated atherosclerosis (As) and high density lipoprotein (HDL) may protect against atherogenesis through multiple pathways. This study was to explore the effect of HDL on the oxLDL uptake in inflammatory adipocytes stimulated by endotoxin lipopolysaccharide (LPS) and the possible mechanism. METHODS AND RESULTS: 3T3-L1 adipocytes were cultured and induced to differentiation and maturation. Acute inflammation in adipocytes was induced by LPS (100 ng/ml) for 6 hours. The adipocytes were pretreated with HDL in various concentrations (10, 50, 100 µg/ml) for 16 hours or with specific PPARγ antagonist (GW9662, 10 µM) or agonist (Rosiglitazone, 10 µM) for 30 min before administration of LPS. The results showed that LPS significantly increased the release of inflammation-related adipokines, such as monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-8 and IL-6, while decreasing the release of leptin and adiponectin. Meanwhile, LPS reduced the uptake and degradation of 125I-oxLDL, and down-regulated the expression of PPARγ and CD36. Pretreatment with HDL dose-dependently affected the release of IL-8 and IL-6 and the reduced uptake and degradation of oxLDL of adipocytes stimulated by LPS, accompanied with marked upregulation of PPARγ and CD36 expression. Pretreatment with GW9662 markedly inhibited the upregulation of CD36 expression mediated by HDL (100 µg/ml), while the effects of Rosiglitazone were opposite to GW9662. CONCLUSIONS: HDL may increase oxLDL uptake of inflammatory adipocytes stimulated by LPS via upregulation of PPARγ/CD36 pathway, which may be a new mechanism of anti-atherosclerosis mediated by HDL.