Cardiovascular Protective Effects Research Articles

Effect of Lipid-Lowering Drugs on Renal and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Dyslipidemia: ARetrospective Cohort Study.

The effects of lipid-lowering drugs (LLDs) on cardiovascular and renal outcomes in patients with advanced chronic kidney disease (CKD) and dyslipidemia are not completely understood. We conducted a retrospective cohort study to evaluate the effect of LLDs on end-stage kidney disease (ESKD), major adverse cardiovascular events (MACEs), and mortality in adult patients with CKD stage 3b, 4, or 5, and dyslipidemia. Participants were recruited between January 1, 2008, and December 31, 2018, and classified as LLD or non-LLD users; the final follow-up date was December 31, 2020. The primary outcome was time to ESKD or death due to renal failure. Sub-distribution hazard regression models adjusted for multivariables, including time-varying lipid profile covariates, were used for the analysis. Among the 6,740 participants, 4,280 patients with CKD and dyslipidemia, including 872 using LLDs and 3,408 not using LLDs, completed the primary analysis. The multivariable analyses showed that LLD users had a significantly lower risk of time to the composite renal outcome (adjusted hazard ratio [aHR], 0.76, 95% confidence interval [CI], 0.65-0.89), and MACE incidence (aHR, 0.75, 95% CI, 0.62-0.93) than did non-LLD users. After adjusting for time-varying covariates of the lipid profile, there was a significant difference in the composite renal outcome (aHR, 0.78, 95% CI, 0.65-0.93) and MACEs (aHR, 0.77, 95% CI, 0.60-0.98). Among adult patients with advanced CKD and dyslipidemia, LLD users had a significantly lower risk of composite renal outcomes and MACEs than non-LLD users. In addition to reducing lipid profile, the use of LLD is associated with renal and cardiovascular protective effects.

Cardiovascular protective effect of sodium-glucose cotransporter 2 inhibitors on patients with acute coronary syndrome and type 2 diabetes mellitus: a retrospective study

BackgroundAcute coronary syndrome (ACS) remains the leading cause of death and disability worldwide, especially when combined with type 2 diabetes mellitus (T2DM). Many multicenter randomized controlled trials have established the cardiovascular benefits of Sodium-Glucose cotransporter 2 inhibitors (SGLT-2i) in patients with T2DM at high cardiovascular risk. However, these studies did not include patients in the early stages of acute coronary events. This study investigated the cardiovascular protective effects of SGLT-2i in patients with ACS and T2DM.MethodsA total of 232 hospitalized patients with ACS and T2DM were enrolled and divided into two groups based on their hypoglycemic drug treatment: the SGLT-2i and the non-SGLT-2i groups. Kaplan–Meier analysis and Cox regression were used to compare adverse cardiovascular outcomes in both groups.ResultsThere were no significant differences in the hospital clinical outcomes between the SGLT-2i and non-SGLT-2i groups. The adverse cardiovascular outcomes did not significantly differ between both groups (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.35–1.25, P = 0.195). Moreover, the rehospitalization rates for ACS or heart failure (HF) were not significantly different between both groups (adjusted HR 0.56, 95%CI 0.28–1.10, P = 0.093). When analyzed separately, there was no significant difference in rehospitalizations for ACS (HR 0.87, 95% CI 0.40–1.87, P = 0.713). However, the SGLT-2i group showed lower rates of rehospitalizations for HF (adjusted HR 0.20, 95% CI 0.04–0.96, P = 0.045). Additionally, there was no significant difference in cardiovascular mortality between both groups (HR 1.75, 95% CI 0.28–10.97, P = 0.543). Notably, the SGLT-2i group exhibited a higher angina symptom control rate than the non-SGLT-2i group (adjusted odd ration (OR) 0.45, 95%CI 0.21–0.93, P = 0.031).ConclusionIn recently diagnosed patients with ACS, who have T2DM, early initiation of SGLT-2i was associated with a lower risk of rehospitalization for HF and a higher rate of angina symptom control.

A novel U-shaped relationship between serum klotho and abdominal aortic calcification in the general population.

Abdominal aortic calcification (AAC) is considered an independent predictor of cardiovascular morbidity and mortality. Klotho, an anti-aging gene, has cardiovascular protective effects. At present, the association between klotho and AAC in the general population is uncertain. We investigated the relationship between serum soluble α-klotho (SSKL) and AAC in 2 327 participants from the National Health and Nutrition Examination Survey. To estimate the association between log-transformed SSKL (lnSSKL) and AAC, multivariate logistic regression analyses were conducted. Stratified analyses were performed to evaluated the potential modifiers. Smoothed curve fitting and generalised additive models were also performed. We found lnSSKL correlated negatively with AAC after adjusting for other confounders. The relationship of lnSSKL with AAC was a U-shaped curve (inflection point: 7.01 pg/ml). On subgroup analyses, stratified by age and smoking habit, the negative correlation of lnSSKL with AAC remained in men and in the population who smoked. Our study revealed a negative relationship between lnSSKL and AAC in the general population. This relationship showed a U-shaped curve and was influenced by age and smoking habit.

Empagliflozin Reverses Oxidized LDL-Induced RECK Suppression, Cardiotrophin-1 Expression, MMP Activation, and Human Aortic Smooth Muscle Cell Proliferation and Migration.

Persistent oxidative stress and inflammation contribute causally to smooth muscle cell (SMC) proliferation and migration, the characteristic features of vascular proliferative diseases. Oxidatively modified low-density lipoproteins (OxLDL) elevate oxidative stress levels, inflammatory responses, and matrix metallopeptidase (MMP) activation, resulting ultimately in SMC migration, proliferation, and phenotype change. Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a membrane-anchored MMP inhibitor. Empagliflozin is an SGLT2 inhibitor and exerts pleiotropic cardiovascular protective effects, including antioxidant and anti-inflammatory effects. Here, we investigated (i) whether OxLDL regulates RECK expression, (ii) whether ectopic expression of RECK reverses OxLDL-induced SMC migration and proliferation, and (iii) whether pretreatment with empagliflozin reverses OxLDL-induced RECK suppression, MMP activation, and SMC migration, proliferation, and differentiation. Indeed, results show that OxLDL at pathophysiological concentration promotes SMC migration and proliferation via NF-κB/miR-30b-dependent RECK suppression. Moreover, OxLDL changed the SMC phenotype to a more pro-inflammatory type, and this effect is blunted by RECK overexpression. Further, treatment with empagliflozin reversed OxLDL-induced miR-30b induction, RECK suppression, MMP activation, SMC migration, proliferation, and proinflammatory phenotype changes. OxLDL-induced cardiotrophin (CT)-1 expression and CT-1 stimulated SMC proliferation and migration in part via leukemia inhibitory factor receptor (LIFR) and glycoprotein 130 (gp130). Ectopic expression of RECK inhibited these effects by physically associating with LIFR and gp130, as evidenced by immunoprecipitation/immunoblotting and double immunofluorescence. Importantly, empagliflozin inhibited CT-1-induced mitogenic and migratory effects. Together, these results suggest the therapeutic potential of sustaining RECK expression or empagliflozin in vascular diseases characterized by SMC proliferation and migration.

The SGLT2 inhibitor empagliflozin attenuates atherosclerosis progression by inducing autophagy.

Cardiovascular disease due to atherosclerosis is one of the leading causes of death worldwide; however, the underlying mechanism has yet to be defined. The sodium-dependent glucose transporter 2 inhibitor (SGLT2i) empagliflozin is a new type of hypoglycemic drug. Recent studies have shown that empagliflozin not only reduces high glucose levels but also exerts cardiovascular-protective effects and slows the process of atherosclerosis. The purpose of this study was to elucidate the mechanism by which empagliflozin ameliorates atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat Western diet to establish an atherosclerosis model. The area and size of atherosclerotic lesions in ApoE-/- mice were then assessed by performing hematoxylin-eosin (HE) staining after empagliflozin treatment. Concurrently, oxidized low-density lipoprotein (oxLDL) was used to mimic atherosclerosis in three different types of cells. Then, following empagliflozin treatment of macrophage cells (RAW264.7), human aortic smooth muscle cells (HASMCs), and human umbilical vein endothelial cells (HUVECs), western blotting was applied to measure the levels of autophagy-related proteins and proinflammatory cytokines, and green fluorescent protein (GFP)-light chain 3 (LC3) puncta were detected using confocal microscopy to confirm autophagosome formation. Oil Red O staining was performed to detect the foaming of macrophages and HASMCs, and flow cytometry was used for the cell cycle analysis. 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), and scratch assays were also performed to examine the proliferation and migration of HASMCs. Empagliflozin suppressed the progression of atherosclerotic lesions in ApoE-/- mice. Empagliflozin also induced autophagy in RAW246.7 cells, HASMCs, and HUVECs via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and it significantly increased the levels of the Beclin1 protein, the LC3B-II/I ratio, and p-AMPK protein. In addition, empagliflozin decreased the expression of P62 and the protein levels of inflammatory cytokines, and it inhibited the foaming of RAW246.7 cells and HASMCs, as well as the expression of inflammatory factors by inducing autophagy. Empagliflozin activated autophagy through the AMPK signaling pathway to delay the progression of atherosclerosis. Furthermore, the results of flow cytometry, EdU assays, CCK-8 cell viability assays, and scratch assays indicated that empagliflozin blocked HASMCs proliferation and migration. Empagliflozin activates autophagy through the AMPK signaling pathway to delay the evolution of atherosclerosis, indicating that it may represent a new and effective drug for the clinical treatment of atherosclerosis.

Elucidating Berberine's Therapeutic and Photosensitizer Potential through Nanomedicine Tools.

Berberine, an isoquinoline alkaloid extracted from plants of the Berberidaceae family, has been gaining interest due to anti-inflammatory and antioxidant activities, as well as neuro and cardiovascular protective effects in animal models. Recently, photodynamic therapy demonstrated successful application in many fields of medicine. This innovative, non-invasive treatment modality requires a photosensitizer, light, and oxygen. In particular, the photosensitizer can selectively accumulate in diseased tissues without damaging healthy cells. Berberine's physicochemical properties allow its use as a photosensitising agent for photodynamic therapy, enabling reactive oxygen species production and thus potentiating treatment efficacy. However, berberine exhibits poor aqueous solubility, low oral bioavailability, poor cellular permeability, and poor gastrointestinal absorption that hamper its therapeutic and photodynamic efficacy. Nanotechnology has been used to minimize berberine's limitations with the design of drug delivery systems. Different nanoparticulate delivery systems for berberine have been used, as lipid-, inorganic- and polymeric-based nanoparticles. These berberine nanocarriers improve its therapeutic properties and photodynamic potential. More specifically, they extend its half-life, increase solubility, and allow a high permeation and targeted delivery. This review describes different nano strategies designed for berberine delivery as well as berberine's potential as a photosensitizer for photodynamic therapy. To benefit from berberine's overall potential, nanotechnology has been applied for berberine-mediated photodynamic therapy.

Association between spicy food and hypertension among Han Chinese aged 30–79 years in Sichuan Basin: a population-based cross-sectional study

BackgroundWhile spicy food is believed to have cardiovascular-protective effects, its impact on hypertension remains uncertain due to conflicting findings from previous studies. This study aimed to explore the association between spicy food and hypertension in Sichuan Basin, China.MethodsThe baseline data of 43,657 residents aged 30–79 in the Sichuan Basin were analyzed including a questionnaire survey (e.g., sociodemographics, diet and lifestyle, medical history), medical examinations (e.g., height, body weight, and blood pressure), and clinical laboratory tests (e.g., blood and urine specimens). Participants were recruited by multi-stage, stratified cluster sampling in consideration of both sex ratio and age ratio between June 2018 and February 2019. Multivariable logistic regression was performed to explore the effect of spicy food on hypertension and multivariable linear regression was applied to estimate the effect of spicy food on systolic and diastolic blood pressure (SBP/DBP).ResultsConcerning hypertension, negative associations with spicy food consumption were observed only in females: compared to those who do not eat spicy food, the odds ratios of consuming spicy food 6–7 days/week, consuming spicy food with strong strength, and years of eating spicy food-to-age ratio were 0.886 (0.799, 0.982), 0.757 (0.587, 0.977), 0.632 (0.505, 0.792), respectively. No significant association was found in males (All P trends > 0.05). In the stratified analyses, participants in the subgroup who were 50 to 79 years old (OR, 95%CI: 0.814, 0.763, 0.869), habitually snored (OR, 95%CI: 0.899, 0.829, 0.976), had a BMI < 24 kg/m2 (OR, 95%CI: 0.886, 0.810, 0.969), had a normal waist circumference (OR, 95%CI: 0.898, 0.810, 0.997), and had no dyslipidemia (OR, 95%CI: 0.897, 0.835, 0.964) showed a significantly stronger association. For SBP, consuming spicy food had negative effects in both genders, but the effect was smaller in males compared to females: among males, the β coefficients for consuming spicy food 1–2 days/week, weak strength, and years of eating spicy food-to-age ratio were 0.931 (-1.832, -0.030), -0.639 (-1.247, -0.032), and − 2.952 (-4.413, -1.492), respectively; among females, the β coefficients for consuming spicy food 3–5 days/week, 6–7 days/week, weak strength, moderate strength, and years of eating spicy food-to-age ratio were − 1.251 (-2.115, -0.388), -1.215 (-1.897, -0.534), -0.788 (-1.313, -0.263), -1.807 (-2.542, -1.072), and − 5.853 (-7.195, -4.512), respectively. For DBP, only a positive association between the years of eating spicy food-to-age ratio and DBP was found in males with β coefficient (95%CI ) of 1.300 (0.338, 2.263); Little association was found in females (all P trends > 0.05), except for a decrease of 0.591 mmHg ( 95%CI: -1.078, -0.105) in DBP among participants who consumed spicy food 1–2 days/week, compared to those who did not consume spicy food.ConclusionSpicy food may lower SBP and has an antihypertensive effect, particularly beneficial for women and individuals with fewer risk factors in the Sichuan Basin. Spicy food consumption may decrease DBP in women but increase it in men. Further multicenter prospective cohort studies are needed to confirm these findings.

Myocardial Priority Promotes Cardiovascular Recovery for Acute Type A Aortic Dissection Combined with Coronary Artery Disease Undergoing Aortic Arch Surgery.

The optimal surgical strategy for acute type A aortic dissection (ATAAD) with coronary artery disease (CAD) remains unclear. The goal of this study was to investigate the cardiovascular protective effects of the myocardial priority (MP) strategy or traditional selective cerebral perfusion (SCP) in ATAAD with CAD. A total of 214 adults were analyzed retrospectively, of which 80 underwent the MP strategy intraoperatively. Seventy-nine pairs were propensity-score-matched and divided into SCP and MP groups. The follow-up period ranged from 6 to 36 months. The MP group had a significantly shorter myocardial ischemic time, higher perfusion flow, higher radial artery pressure, and lower incidence of NIRS decrease >20% of the base value, but a longer lower limb circulatory arrest and bypass time than the SCP group. Although similar adverse cardiac and cerebrovascular events were observed in both groups, a shorter posthospital stay, less blood loss and transfusion, higher postoperative hemoglobin, lower creatinine, and higher PaO2/FiO2 were observed in the MP group. Subgroup analysis showed that when the TIMI Risk Score was <4, the MP group had a lower incidence of low cardiac output and lower postoperative cTnI level. The follow-up patients had similar morbidities between the two groups. The novel MP strategy is associated with a shortened myocardial ischemic time, better maintained perfusion of vital organs, and postoperative recovery after surgery for ATAAD combined with non-severe CAD.

Riboflavin protects against heart failure via SCAD-dependent DJ-1-Keap1-Nrf2 signalling pathway.

Our recent studies have shown that flavin adenine dinucleotide (FAD) exerts cardiovascular protective effects by supplementing short-chain acyl-CoA dehydrogenase (SCAD). The current study aimed to elucidate whether riboflavin (the precursor of FAD) could improve heart failure via activating SCAD and the DJ-1-Keap1-Nrf2 signalling pathway. Riboflavin treatment was given to the mouse transverse aortic constriction (TAC)-induced heart failure model. Cardiac structure and function, energy metabolism and apoptosis index were assessed, and relevant signalling proteins were analysed. The mechanisms underlying the cardioprotection by riboflavin were analysed in the cell apoptosis model induced by tert-butyl hydroperoxide (tBHP). In vivo, riboflavin ameliorated myocardial fibrosis and energy metabolism, improved cardiac dysfunction and inhibited oxidative stress and cardiomyocyte apoptosis in TAC-induced heart failure. In vitro, riboflavin ameliorated cell apoptosis in H9C2 cardiomyocytes by decreasing reactive oxygen species (ROS). At the molecular level, riboflavin significantly restored FAD content, SCAD expression and enzymatic activity, activated DJ-1 and inhibited the Keap1-Nrf2/HO1 signalling pathway in vivo and in vitro. SCAD knockdown exaggerated the tBHP-induced DJ-1 decrease and Keap1-Nrf2/HO1 signalling pathway activation in H9C2 cardiomyocytes. The knockdown of SCAD abolished the anti-apoptotic effects of riboflavin on H9C2 cardiomyocytes. DJ-1 knockdown hindered SCAD overexpression anti-apoptotic effects and regulation on Keap1-Nrf2/HO1 signalling pathway in H9C2 cardiomyocytes. Riboflavin exerts cardioprotective effects on heart failure by improving oxidative stress and cardiomyocyte apoptosis via FAD to stimulate SCAD and then activates the DJ-1-Keap1-Nrf2 signalling pathway.

Emerging evidence for a cardiovascular protective effect of concentrated Japanese plum juice.

Emerging evidence for a cardiovascular protective effect of concentrated Japanese plum juice.

Cardioprotective effects of arjunolic acid in LPS-stimulated H9C2 and C2C12 myotubes via the MyD88-dependent TLR4 signaling pathway

Context Arjunolic acid (AA) is a triterpenoid saponin found in Terminalia arjuna (Roxb.) Wight & Arn. (Combretaceae). It exerts cardiovascular protective effects as a phytomedicine. However, it is unclear how AA exerts the effects at the molecular level. Objective This study investigates the cardioprotective effects of arjunolic acid (AA) via MyD88-dependant TLR4 downstream signaling marker expression. Materials and methods The MTT viability assay was used to assess the cytotoxicity of AA. LPS induced in vitro cardiovascular disease model was developed in H9C2 and C2C12 myotubes. The treatment groups were designed such as control (untreated), LPS control, positive control (LPS + pyrrolidine dithiocarbamate (PDTC)-25 µM), and treatment groups were co-treated with LPS and three concentrations of AA (50, 75, and 100 µM) for 24 h. The changes in the expression of TLR4 downstream signaling markers were evaluated through High Content Screening (HCS) and Western Blot (WB) analysis. Results After 24 h of co-treatment, the expression of TLR4, MyD88, MAPK, JNK, and NF-κB markers were upregulated significantly (2-6 times) in the LPS-treated groups compared to the untreated control in both HCS and WB experiments. Evidently, the HCS analysis revealed that MyD88, NF-κB, p38, and JNK were significantly downregulated in the H9C2 myotube in the AA treated groups. In HCS, the expression of NF-κB was downregulated in C2C12. Additionally, TLR4 expression was downregulated in both H9C2 and C2C12 myotubes in the WB experiment. Discussion and conclusions TLR4 marker expression in H9C2 and C2C12 myotubes was subsequently decreased by AA treatment, suggesting possible cardioprotective effects of AA.

Improvement in Endothelial Function in Men Taking Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction

BackgroundThe purpose of this research was to explore the mechanistic protective cardiovascular effects of phosphodiesterase-5 inhibitors (PDE5-Is) in males with erectile dysfunction. Erectile dysfunction and endothelial dysfunction both precede clinical atherosclerosis. Studies have shown that treatment for erectile dysfunction with PDE5-Is decreased death, heart failure, myocardial infarction, and revascularization in males with erectile dysfunction who had previous myocardial infarction, and cardiovascular events. MethodsThis was a pilot study that recruited 5 men with erectile dysfunction without cardiovascular disease. Endothelial function (flow-mediated percent change of the diameter of the brachial artery), erectile dysfunction grade, high-sensitivity C-reactive protein, and body mass index were measured before and 3 months after starting treatment with tadalafil, 5 mg daily. Pearson's analysis was performed to study a correlation between the change in erectile dysfunction and the change in endothelial function. ResultsA significant correlation was found between changes in flow-mediated percent change of the diameter of the brachial artery and changes in erectile dysfunction following the administration of tadalafil (P = .010; Pearson correlation coefficient = 0.959). No change was observed in C-reactive protein or weight. ConclusionsErectile dysfunction and endothelial dysfunction are risk factors for cardiovascular disease. Our study showed that PDE5-Is improved endothelial function and erectile dysfunction (with a significant correlation). Improving endothelial function could be the mechanism that leads to a reduction in cardiovascular events and death in men with erectile dysfunction treated with PDE5-Is.

Efficacy of sacubitril-valsartan and SGLT2 inhibitors in heart failure with reduced ejection fraction: A systematic review and meta-analysis.

Sacubitril-valsartan (SV) monotherapy has been shown to help patients with Heart failure with reduced ejection fraction (HFrEF), but whether adding a sodium-glucose cotransporter-2 inhibitor (SGLT2i) improves treatment results even more is unknown. The goal of this study was to look at the efficacy of SV with additional SGLT2i in HFrEF patients. For this study, several databases, such as PubMed, EMBASE, Web of Science, and the Cochrane Library, were searched. A coherent search approach was used for data extraction. Review Manager 5.2 and MedCalc were used for conducting the meta-analysis and bias analysis. A meta-regression study correlates patient mean age with primary and secondary outcomes. Seven trials totaling 16 100 patients were included in this meta-analysis. All-cause mortality, cardiovascular mortality, and improvement in mean left ventricular ejection fraction (LVEF) were the study's major objectives, while hospitalization for heart failure (HF) was calculated to be its secondary outcome. Our analysis showed that HFrEF patients receiving the combination of SV and SGLT2i had better treatment outcomes than the standard SV monotherapy, with risk ratios of 0.76 (0.65-0.88) for all-cause mortality, 0.65 (0.49-0.86) for cardiovascular mortality, 1.41 (-0.59 to 3.42) for change in mean LVEF, and 0.80 (0.64-1.01) for hospitalization for HF. According to the regression analysis, older HFrEF patients have higher rates of hospitalization, cardiovascular disease, and overall death. The combination of SV and SGLT2i may have a greater cardiovascular protective effect and minimize the risk of death or hospitalization due to heart failure in HFrEF.

Myocardial infarction model induced by isoproterenol in rats and potential cardiovascular protective effect of a nattokinase-containing hard capsule

BackgroundTD.HK01® consists of a Japanese traditional medicine: Nattokinase (derived from soybean) and three other natural components, namely dried Hirudo medicinalis, Semen Mucuna interrupta and Huperzia carinata. ObjectivesTD.HK01® is potentially aimed to the preventive treatment of cardiovascular disease (CVD) in general, and myocardial infarction (MI) in particular. MethodsIn this study, a non-invasive method has been used to induce MI in rats, preceded by oral administration of TD.HK01® for 30 consecutive days to determine the potential cardiovascular effect of this pretreatment. Rats were divided into four groups: normal control group, ISO-induced group (isoproterenol (ISO), 150 mg/kg, s.c.) and two groups treated by TD.HK01® in different doses (0.31 and 0.92 g/kg, orally + ISO 150 mg/kg, s.c.). ResultsTD.HK01® treated groups showed significant improvement as in abnormal electrocardiography (ECG) alteration ratio, in decreased biochemical specific markers troponin T and in decreased non-specific biochemical markers (LDH and AST) between each of TD.HK01® treated groups and ISO-induced group. The effect on vascular system was also evaluated through serum eNOS quantification and a notable increase in an anti-oxidative enzyme catalase. All three groups, except the normal control one, had pathological lesions in histopathology in different levels - modest injuries in treated groups and more severe in ISO-induced group. ConclusionsIt is concluded on the basis of the findings that isoproterenol induced MI in all three groups and TD.HK01® did have its potential protective effect in vivo on cardiovascular system.

Hyperoside Nanomicelles Alleviate Atherosclerosis by Modulating the Lipid Profile and Intestinal Flora Structure in High-Fat-Diet-Fed Apolipoprotein-E-Deficient Mice.

Atherosclerosis (AS) is a serious threat to human health and the main pathological basis of cardiovascular disease. Hyperoside (Hyp), a flavonoid found mainly in traditional Chinese herbs, can exert antitumor, anti-inflammatory, antioxidant, and cardiovascular-protective effects. Herein, we prepared hybrid nanomicelles (HFT) comprising Hyp loaded into pluronic F-127 and polyethylene glycol 1000 vitamin E succinate and assessed their effects on AS. To establish an AS model, apolipoprotein-E-deficient (ApoE-/-) mice were fed a high-fat diet. We then analyzed the effects of HFT on AS-induced changes in aortic tissues and metabolic markers, simultaneously assessing changes in gut flora community structure. In mice with AS, HFT significantly reduced the aortic plaque area; decreased levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, inflammatory factors, and inducible nitric oxide synthase (NOS); increased high-density lipoprotein cholesterol, endothelial NOS, superoxide dismutase, catalase, and glutathione levels; and promoted the proliferation of beneficial gut bacteria. HFT could regulate intestinal flora structure and lipid metabolism and inhibit inflammatory responses. These beneficial effects may be mediated by inhibiting nuclear factor kappa B signal activation, reducing inflammatory factor expression and improving gut microflora structure and dyslipidemia. The present study provides an empirical basis for the development and clinical application of new dosage forms of Hyp.

Integration of metabolomics and network pharmacology to reveal the protective mechanism underlying Wogonoside in acute myocardial ischemia rats

Ethnopharmacological relevanceIn traditional medicine, both Scutellaria baicalensis Georgi (SBG) and the traditional formulas composed of it have been used to treat a wide range of diseases, including cancer and cardiovascular. Wogonoside (Wog) is the biologically active flavonoid compound extracted from the root of SBG, with potential cardiovascular protective effects. However, the mechanisms underlying the protective effect of Wog on acute myocardial ischemia (AMI) have not yet been clearly elucidated. Aim of the studyTo explore the protective mechanism of Wog on AMI rats by comprehensively integrating traditional pharmacodynamics, metabolomics, and network pharmacology. MethodsThe rat was pretreatment with Wog at a dose of 20 mg/kg/d and 40 mg/kg/d once daily for 10 days and then ligated the left anterior descending coronary artery of rats to establish the AMI rat model. Electrocardiogram (ECG), cardiac enzyme levels, heart weight index (HWI), Triphenyltetrazolium chloride (TTC) staining, and histopathological analyses were adopted to evaluate the protective effect of Wog on AMI rats. Moreover, a serum metabolomic-based UHPLC-Q-Orbitrap MS approach was performed to find metabolic biomarkers and metabolic pathways, and network pharmacology analysis was applied to predict targets and pathways of Wog in treating AMI. Then, the network pharmacology and metabolomic results were integrated to elucidate the mechanism of Wog in treating AMI. Finally, RT- PCR was used to detect the mRNA expression levels of PTGS1, PTGS2, ALOX5, and ALOX15 to validate the result of integrated metabolomics and network analysis. ResultsPharmacodynamic studies suggest that Wog could effectively prevent the ST-segment of electrocardiogram elevation, reduce the myocardial infarct size, heart weight index, and cardiac enzyme levels, and alleviate cardiac histological damage in AMI rats. Metabolomics analysis showed that the disturbances of metabolic profile in AMI rats were partly corrected by Wog and the cardio-protection effects on AMI rats involved 32 differential metabolic biomarkers and 4 metabolic pathways. In addition, the integrated analysis of network pharmacology and metabolomics showed that 7 metabolic biomarkers, 6 targets, and 6 crucial pathways were the main mechanism for the therapeutic application of Wog for AMI. Moreover, the results of RT-PCR showed that PTGS1, PTGS2, ALOX5, and ALOX15 mRNA expression levels were reduced after treatment with Wog. ConclusionWog exerts cardio-protection effects on AMI rats via the regulation of multiple metabolic biomarkers, multiple targets, and multiple pathways, our current study will provide strong scientific evidence supporting the therapeutic application of Wog for AMI.

790-P: An Indirect Treatment Comparison of the Cardiovascular Protective Effect of Semaglutide vs. Liraglutide in Subjects with Type 2 Diabetes

Background: In the absence of head-to-head evidence, an indirect treatment comparison (ITC) using individual-level participant data was conducted to provide evidence of the comparative cardiovascular (CV) protective effect of liraglutide vs semaglutide in subjects with type 2 diabetes. Methods: CV outcomes trials (CVOTs) were identified for comparators of interest. LEADER was a randomised controlled trial studying the CV protective effect of liraglutide vs placebo. Similarly, two CVOTs comparing semaglutide with placebo were identified: SUSTAIN 6 and PIONEER 6. Time to first 3-point major adverse CV events (3P-MACE) (adjudicated) was the primary outcome in all trials and was chosen as the primary outcome for the ITC. Potential effect modifiers (baseline indicators of prior CV disease, albumin:creatinine ratio, estimated glomerular filtration rate) were identified in the literature and adjusted for in the ITC. A fixed-effects ITC using individual participant data was conducted in a Bayesian setting. Missing data for potential effect modifiers were imputed using multiple imputation (20 imputations). Comparisons were summarised as cause-specific hazard ratios (HRs). Population-average relative treatment effects between liraglutide and semaglutide were reported for each of the three populations corresponding to the three studies. Results: The ITC showed that the relative risk of semaglutide vs liraglutide for the occurrence of 3P-MACE in the LEADER population favoured semaglutide: HR 0.73 (95% credible interval [CrI]: 0.56;0.94); results also favoured semaglutide in the SUSTAIN 6 (HR 0.76 [95% CrI: 0.59;0.97]) and PIONEER 6 (HR 0.78 [95% CrI: 0.60;1.00]) populations. Conclusion: The results demonstrated a risk reduction of CV events (3P-MACE) for semaglutide vs liraglutide of 22-27% depending on the population studied. These results may have implications for clinical practice. Disclosure B.Chubb: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. M.Bøg: Employee; Lundbeck, Novo Nordisk.

840-P: Dual Amylin and Calcitonin Receptor Agonist Treatment Improves Blood Pressure and Glucose Control in ZSF1 Rats

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on both body weight, glucose control and insulin action. However, whether DACRAs affect hypertension, and diabetes-related cardiovascular complications remain unknown. In this study, the cardiovascular protective effect of the DACRA KBP-336 was evaluated in obese Zucker diabetic fatty-Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Obese ZSF1 rats were treated for 60 days with the KBP-336 (4.5 nmol/kg Q3D) and treatment efficacy on glucose control and blood pressure measured by tail cuff was evaluated. Furthermore, serum biomarkers of cardiovascular complications were evaluated. KBP-336 treatment significantly lowered fasting blood glucose levels compared to vehicle (P&amp;lt;0.001). This was also illustrated in the HbA1c levels at study end, where KBP-336 resulted in significantly (P&amp;lt;0.001) lower levels than vehicle. Importantly, KBP-336 significantly reduced both systolic (AUC levels reduced by 13.3%, P&amp;lt;0.001) and diastolic (AUC levels reduced by 17.0%, P&amp;lt;0.001) blood pressure compared to vehicle without affecting the heart rate. Notably, the beneficial effects on both glucose control and blood pressure were obtained independent of weight loss as KBP-336 only resulted in a small and transient weight reduction. Furthermore, serum levels of the marker of cardiovascular disease, rPRO-C6 (collagen type VI formation marker) were 6.4% lower in KBP-336 treated rats compared to vehicle, supporting improvement in cardiovascular parameters. In summary, we show for the first time that KBP-336 benefits blood pressure in a metabolic rat model suffering from hypertension. In addition, KBP-336 improved glucose control independent of weight loss. These data highlight KBP-336 as a promising candidate for treating obesity and related comorbidities including type 2 diabetes and hypertension. Disclosure S.A.Melander: None. A.T.Larsen: Employee; Nordic Bioscience A/S. K.Mohamed: Employee; Nordic Bioscience. M.A.Karsdal: Speaker's Bureau; Pfizer Inc. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S. Funding Danish Research Foundation; Innovation Fund Denmark; European Union’s Horizon 2020 Research and Innovation Program (814244)

Salvianolic acids from Salvia miltiorrhiza Bunge and their anti-inflammatory effects through the activation of α7nAchR signaling

Ethnopharmacological relevanceCardiovascular disease (CVD) is a serious disease with a high incidence rate and mortality. Inflammation is closely related to the occurrence of CVDs. As an essential medicine of promoting blood circulation and removing blood stasis in China, Salvia miltiorrhiza Bunge (Danshen) is widely used to treat CVDs due to its anti-inflammatory and cardiovascular protective effects. Salvianolic acids are the most abundant component in the water extract of S. miltiorrhiza, which has a significant effect on the treatment of CVDs. However, due to the complex composition of salvianolic acids, the active molecules and their underlying mechanisms have not been fully explored. Aim of this studyThe present study aims to isolate and identify salvianolic acids from Danshen with anti-inflammatory activity and explore the potential mechanisms of isolates. MethodsThe structures of isolated salvianolic acids were elucidated by UV, IR, NMR, MS and electronic circular dichroism (ECD) calculations. Then anti-inflammatory activities of isolates were screened out by the zebrafish inflammation models. The most active compound was further used to explore the anti-inflammatory mechanisms on LPS-stimulated RAW 264.7 cells. The key inflammatory cytokines IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). The protein expression levels of STAT3, p-STAT3 (Tyr705), NF-κB p65, IκBα, p-IκBα (Ser32) and α7nAchR were determined by Western blotting. The nuclear translocation of p-STAT3 (Tyr705) and NF-κB p65 was evaluated by immunofluorescence assays. Finally, the in vivo anti-inflammatory mechanisms were investigated by observation of neutrophil migration, H&E staining, survival analysis and quantitative PCR (Q-PCR) in LPS-microinjected zebrafish. ResultsTwo new and four known compounds were isolated from Danshen. Among them, isosalvianolic acid A-1 (C1) and ethyl lithospermate (C5) inhibited neutrophil migrations in three zebrafish inflammation models and C1 with the best activities decreased the secretion of IL-6 and TNF-α and inhibited the expression level of p-IκBα (Ser32) in LPS stimulated RAW 264.7 cells. In addition, C1 also reduced the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705). Moreover, C1 significantly upregulated the protein expression of α7nAchR, and the knockdown of α7nAchR counteracted the effects of C1 on the production of IL-6 and TNF-α and the expression levels of p-STAT3 (Tyr705), NF-κB p65 and p-IκBα (Ser32). In vivo experiments, C1 decreased the migration and infiltration of inflammatory cells, increased the survival ratio and inhibited the mRNA level of IL-6, TNF-α, STAT3, NF-κB and IκBα in LPS-microinjected zebrafish. ConclusionTwo new and four known compounds were isolated from Danshen. Among them, C1 exerted anti-inflammatory activities by activating α7nAchR signaling and subsequently inhibiting STAT3 and NF-κB pathways. This study provided evidence for the clinical application of Danshen and contributed to the development of C1 as a novel in the treatment of cardiovascular disease.

Untargeted Metabolomics Analysis Revealed the Difference of Component and Geographical Indication Markers of Panax notoginseng in Different Production Areas.

Panax notoginseng (P. notoginseng) has excellent medicinal and food dual-use characteristics. However, P. notoginseng with a unique origin label has become the target of fraud because of people confusing or hiding its origin. In this study, an untargeted nuclear magnetic resonance (NMR)-based metabolomics approach was used to discriminate the geographical origins of P. notoginseng from four major producing areas in China. Fifty-two components, including various saccharides, amino acids, saponins, organic acids, and alcohols, were identified and quantified through the NMR spectrum, and the area-specific geographical identification components were further screened. P. notoginseng from Yunnan had strong hypoglycemic and cardiovascular protective effects due to its high acetic acid, dopamine, and serine content, while P. notoginseng from Sichuan was more beneficial for diseases of the nervous system because of its high content of fumarate. P. notoginseng from Guizhou and Tibet had high contents of malic acid, notoginsenoside R1, and amino acids. Our results can help to distinguish the geographical origin of P. notoginseng and are readily available for nutritional recommendations in human consumption.