Effect of Coenzyme Q10 Supplementation on Vascular Endothelial Function: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Coenzyme Q10 (CoQ10) has gained attention as a potential therapeutic agent for improving endothelial function. Several randomized clinical trials have investigated CoQ10 supplementation's effect on endothelial function. However, these studies have yielded conflicting results, therefore this systematic review and meta-analysis were conducted. AIM: This systematic review and meta-analysis were conducted to assess the effects of CoQ10 supplementation on endothelial factors. METHODS: A comprehensive search was done in numerous databases until July 19th, 2023. Quantitative data synthesis was performed using a random-effects model, with weight mean difference (WMD) and 95% confidence intervals (CI). Standard methods were used for the assessment of heterogeneity, meta-regression, sensitivity analysis, and publication bias. RESULTS: 12 studies comprising 489 subjects were included in the meta-analysis. The results demonstrated significant increases in Flow Mediated Dilation (FMD) after CoQ10 supplementation (WMD: 1.45; 95% CI: 0.55 to 2.36; p < 0.02), but there is no increase in Vascular cell adhesion protein (VCAM), and Intercellular adhesion molecule (ICAM) following Q10 supplementation (VCAM: SMD: - 0.34; 95% CI: - 0.74 to - 0.06; p < 0.10) (ICAM: SMD: - 0.18; 95% CI: - 0.82 to 0.46; p < 0.57). The sensitivity analysis showed that the effect size was robust in FMD and VCAM. In meta-regression, changes in FMD percent were associated with the dose of supplementation (slope: 0.01; 95% CI: 0.004 to 0.03; p = 0.006). CONCLUSIONS: CoQ10 supplementation has a positive effect on FMD in a dose-dependent manner. Our findings show that CoQ10 has an effect on FMD after 8 weeks of consumption. Additional research is warranted to establish the relationship between CoQ10 supplementation and endothelial function.

Preservation of Adrenoceptor and Endothelin Receptor Mediated Vasoconstriction and of Endothelium-Dependent Relaxation after Cold Storage of Explanted Blood Vessels for ex vivo Analyses.

INTRODUCTION: Adrenoceptor and endothelin (ET) receptor-mediated vasoconstriction as well as endothelium-dependent vasodilation of human saphenous veins were compared before and after 20 h of cold storage. METHODS: Contractile responses to potassium chloride (KCl), norepinephrine (NE), and ET-1 as well as vasodilator responses to acetylcholine (ACh) were evaluated. RESULTS: Storage in HEPES-supplemented Dulbecco's modified Eagle's medium (HDMEM) diminished KCl induced contractile forces to 71% (p = 0.002) and NE induced contractions to 80% (p = 0.037), in contrast to HEPES-supplemented Krebs-Henseleit solution (HKH) and TiProtec solution. KCl-normalized NE contractions were not affected by storage. NE EC50 values were slightly lower (7.1E-8 vs. 7.5E-8, p = 0.019) after storage in HKH, with no changes after storage in the other solutions. Endothelium-dependent responses to ACh were not affected by storage. ET-1 induced contractions were attenuated after storage in HDMEM (77%, p = 0.002), HKH (75%, p = 0.020), and TiProtec (73%, p = 0.010) with no changes in normalized constrictions. ET-1 EC50 values were not affected by storage. CONCLUSION: Loss of contractility after storage in HDMEM may reflect the lower content of dextrose. There was no specific attenuation of adrenoceptor, ET-receptor, or ACh receptor mediated signal transduction after storage in any of the media. HKH or TiProtec are equally suitable cold storage solutions for ex vivo measurements.

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. RESULTS: Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. CONCLUSIONS: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3.

Therapeutic effect of Danhong injection on diabetic patients with cerebral infarction and its influence on vascular endothelial function and hemodynamics.

To investigate the therapeutic effect of Danhong injection on diabetic patients with cerebral infarction and its influence on vascular endothelial function and hemodynamic level. A total of 100 diabetic patients with cerebral infarction admitted to our hospital from November 2019 to November 2020 were identified as the research subjects and randomly divided into a control group given routine treatment and a study group treated with Danhong injection, with 50 cases in each group. The efficiency of the two groups on vascular endothelial function, blood glucose level, National Institute of Health Stroke Scale (NIHSS) score, the incidence of adverse reactions, and hemodynamic indicators were compared. Most (98%) of patients in the study group displayed effective outcomes, which was significantly better than that in the control group. The study group outperformed the control study group in the vascular endothelial function, blood glucose level, NIHSS score and hemodynamic indicators (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). Danhong injection obtains a promising therapeutic effect on diabetic patients with cerebral infarction, as it significantly improves the vascular endothelial function and hemodynamic level.

Endothelial SIRT1 as a Target for the Prevention of Arterial Aging: Promises and Challenges.

ABSTRACT: SIRT1, a member of the sirtuin family of longevity regulators, possesses potent activities preventing vascular aging. The expression and function of SIRT1 in endothelial cells are downregulated with age, in turn causing early vascular aging and predisposing various vascular abnormalities. Overexpression of SIRT1 in the vascular endothelium prevents aging-associated endothelial dysfunction and senescence, thus the development of hypertension and atherosclerosis. Numerous efforts have been directed to increase SIRT1 signaling as a potential strategy for different aging-associated diseases. However, the complex mechanisms underlying the regulation of SIRT1 have posed a significant challenge toward the design of specific and effective therapeutics. This review aimed to provide a summary on the regulation and function of SIRT1 in the vascular endothelium and to discuss the different approaches targeting this molecule for the prevention and treatment of age-related cardiovascular and cerebrovascular diseases.

A novel evaluation of endothelial dysfunction ex vivo: "Teaching an Old Drug a New Trick".

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Many CVDs begin with endothelium dysfunction (ED), including hypertension, thrombosis, and atherosclerosis. Our assay evaluated ED in isolated murine aorta by quantifying phenylephrine-induced contractions (PE) in the presence of L-NAME, which blocked acetylcholine-induced relaxation (ACh %; >99%). The "L-NAME PE Contraction Ratio" (PECR) was defined as: "PE Tension post-L-NAME" divided by "PE Tension pre-L-NAME." We hypothesized that our novel PE Contraction Ratio would strongly correlate with alterations in endothelium function. Validation 1: PECR and ACh % values of naïve aortas were strongly and positively correlated (PECR vs. ACh %, r2  = 0.91, n = 7). Validation 2: Retrospective analyses of published aortic PECR and ACh % data of female mice exposed to filtered air, propylene glycol:vegetable glycerin (PG:VG), formaldehyde (FA), or acetaldehyde (AA) for 4d showed that the PECR in air-exposed mice (PECR = 1.43 ± 0.05, n = 16) correlated positively with the ACh % (r2  = 0.40) as seen in naïve aortas. Similarly, PECR values were significantly decreased in aortas with ED yet retained positive regression coefficients with ACh % (PG:VG r2  = 0.54; FA r2  = 0.55). Unlike other toxicants, inhaled AA significantly increased both PECR and ACh % values yet diminished their correlation (r2  = 0.09). Validation 3: To assess species-specific dependence, we tested PECR in rat aorta, and found PECR correlated with ACh % relaxation albeit less well in this aged and dyslipidemic model. Because the PECR reflects NOS function directly, it is a robust measure of both ED and vascular dysfunction. Therefore, it is a complementary index of existing tests of ED that also provides insight into mechanisms of vascular toxicity.

Effect of hyperbaric oxygen combined with alprostadil in the treatment of elderly diabetic nephropathy and effects on serum miR-126 and miR-342 levels.

This study aims to investigate the effect of hyperbaric oxygen combined with alprostadil in the treatment of elderly diabetic nephropathy (DN) and its effect on serum miR-126 and miR-342 levels. The total effective rate of the study group was 91.53% after treatment, which was higher than that (74.58%) of the control group (p<0.05); the levels of UAER, Scr, BUN and HbA1c, FPG, 2h PG were lowered in the two groups after treatment, and the levels of these indexes were lower in the study group than those in the control group (p<0.05); the levels of vWF, ET-1, CD8+, miR-342 were lowered after treatment for the two groups, and the levels of these indexes were lower in the study group than those in the control group; the levels of NO, CD3+, CD4+ and miR-126 were increased after treatment and the levels were higher in the study group than those in the control group (p<0.05). The application of hyperbaric oxygen combined with alprostadil in the treatment of elderly DN patients can improve renal function, lower blood glucose, improve vascular endothelial function and immune function, adjust serum miR-126 and miR-342 levels, thereby increasing curative effect.

Vitamin D deficiency attenuates endothelial function by reducing antioxidant activity and vascular eNOS expression in the rat microcirculation.

This study examined the effects of vitamin D deficiency on vascular function and tissue oxidative status in the microcirculation; and whether or not these effects can be ameliorated with calcitriol, the active vitamin D metabolite. Three groups (n = 10 each) of male Sprague Dawley rats were fed for 10 weeks with control diet (CR), vitamin D-deficient diet without (DR), or with oral calcitriol supplementation (0.15 µg/kg) for the last four weeks (DSR). After 10 weeks, rats were sacrificed; mesenteric arterial rings were studied using wire myograph. Oxidative stress biomarkers malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured in the mesenteric arterial tissue. Vascular protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blotting. Acetylcholine-induced endothelium-dependent relaxation of DR was lower than CR. eNOS expression and SOD activity were lower in mesenteric arterial tissue of DR compared to CR. Calcitriol supplementation to DSR did not ameliorate the above parameters; in fact, augmented endothelium-dependent contraction was observed. Serum calcium was higher in DSR compared to CR and DR. In conclusion, vitamin D deficiency impaired microvascular vasodilation, associated with eNOS downregulation and reduced antioxidant activity. Calcitriol supplementation to vitamin D-deficient rats at the dosage used augmented endothelium-dependent contraction, possibly due to hypercalcaemia.

Time-Efficient Inspiratory Muscle Strength Training Lowers Blood Pressure and Improves Endothelial Function, NO Bioavailability, and Oxidative Stress in Midlife/Older Adults With Above-Normal Blood Pressure.

Background High-resistance inspiratory muscle strength training (IMST) is a novel, time-efficient physical training modality. Methods and Results We performed a double-blind, randomized, sham-controlled trial to investigate whether 6 weeks of IMST (30 breaths/day, 6 days/week) improves blood pressure, endothelial function, and arterial stiffness in midlife/older adults (aged 50-79 years) with systolic blood pressure ≥120 mm Hg, while also investigating potential mechanisms and long-lasting effects. Thirty-six participants completed high-resistance IMST (75% maximal inspiratory pressure, n=18) or low-resistance sham training (15% maximal inspiratory pressure, n=18). IMST was safe, well tolerated, and had excellent adherence (≈95% of training sessions completed). Casual systolic blood pressure decreased from 135±2 mm Hg to 126±3 mm Hg (P<0.01) with IMST, which was ≈75% sustained 6 weeks after IMST (P<0.01), whereas IMST modestly decreased casual diastolic blood pressure (79±2 mm Hg to 77±2 mm Hg, P=0.03); blood pressure was unaffected by sham training (all P>0.05). Twenty-four hour systolic blood pressure was lower after IMST versus sham training (P=0.01). Brachial artery flow-mediated dilation improved ≈45% with IMST (P<0.01) but was unchanged with sham training (P=0.73). Human umbilical vein endothelial cells cultured with subject serum sampled after versus before IMST exhibited increased NO bioavailability, greater endothelial NO synthase activation, and lower reactive oxygen species bioactivity (P<0.05). IMST decreased C-reactive protein (P=0.05) and altered select circulating metabolites (targeted plasma metabolomics) associated with cardiovascular function. Neither IMST nor sham training influenced arterial stiffness (P>0.05). Conclusions High-resistance IMST is a safe, highly adherable lifestyle intervention for improving blood pressure and endothelial function in midlife/older adults with above-normal initial systolic blood pressure. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03266510.

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 µM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

Mammalian Arginase Inhibitory Activity of Methanolic Extracts and Isolated Compounds from Cyperus Species.

Polyphenolic enriched extracts from two species of Cyperus, Cyperus glomeratus and Cyperus thunbergii, possess mammalian arginase inhibitory capacities, with the percentage inhibition ranging from 80% to 95% at 100 µg/mL and 40% to 64% at 10 µg/mL. Phytochemical investigation of these species led to the isolation and identification of two new natural stilbene oligomers named thunbergin A-B (1-2), together with three other stilbenes, trans-resveratrol (3), trans-scirpusin A (4), trans-cyperusphenol A (6), and two flavonoids, aureusidin (5) and luteolin (7), which were isolated for the first time from C.thunbergii and C. glomeratus. Structures were established on the basis of the spectroscopic data from MS and NMR experiments. The arginase inhibitory activity of compounds 1-7 was evaluated through an in vitro arginase inhibitory assay using purified liver bovine arginase. As a result, five compounds (1, 4-7) showed significant inhibition of arginase, with IC50 values between 17.6 and 60.6 µM, in the range of those of the natural arginase inhibitor piceatannol (12.6 µM). In addition, methanolic extract from Cyperus thunbergii exhibited an endothelium and NO-dependent vasorelaxant effect on thoracic aortic rings from rats and improved endothelial dysfunction in an adjuvant-induced arthritis rat model.

Nanotechnological approach to delivering nutraceuticals as promising drug candidates for the treatment of atherosclerosis.

Atherosclerosis is Caesar's sword, which poses a huge risk to the present generation. Understanding the atherosclerotic disease cycle would allow ensuring improved diagnosis, better care, and treatment. Unfortunately, a highly effective and safe way of treating atherosclerosis in the medical community remains a continuous challenge. Conventional treatments have shown considerable success, but have some adverse effects on the human body. Natural derived medications or nutraceuticals have gained immense popularity in the treatment of atherosclerosis due to their decreased side effects and toxicity-related issues. In hindsight, the contribution of nutraceuticals in imparting enhanced clinical efficacy against atherosclerosis warrants more experimental evidence. On the other hand, nanotechnology and drug delivery systems (DDS) have revolutionized the way therapeutics are performed and researchers have been constantly exploring the positive effects that DDS brings to the field of therapeutic techniques. It could be as exciting as ever to apply nano-mediated delivery of nutraceuticals as an additional strategy to target the atherosclerotic sites boasting high therapeutic efficiency of the nutraceuticals and fewer side effects.

Calcitriol Supplementation Ameliorates Microvascular Endothelial Dysfunction in Vitamin D-Deficient Diabetic Rats by Upregulating the Vascular eNOS Protein Expression and Reducing Oxidative Stress.

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 µg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.

Pyrogallol-Phloroglucinol-6 6-Bieckol on Attenuates High-Fat Diet-Induced Hypertension by Modulating Endothelial-to-Mesenchymal Transition in the Aorta of Mice.

Endothelial-to-mesenchymal transition (EndMT), which is involved in the development of various cardiovascular diseases, is induced by dyslipidemia or obesity. In dyslipidemia, the increased levels of oxidized low-density lipoproteins (oxLDL) upregulated the lectin-type oxidized LDL receptor 1 (Lox-1), which then upregulated the down signaling pathways of PKC-α/MMPs/TGF-ß/SMAD2 or 3 and increased the EndMT. In this study, we investigated the effect of pyrogallol-phloroglucinol-6,6-bieckol (PPB), which is a compound of Ecklonia cava (E. cava), on decreased blood pressure (BP) by attenuating the EndMT in a high-fat diet- (HFD-) fed animal model. We also investigated PPB's attenuation effect on EndMT in oxLDL-treated mouse endothelial cells as an in vitro model. The results indicated that, in the aorta or endothelial cells of mice, the HFD or oxLDL treatment significantly increased the expression of Lox-1/PKC-α/MMP9/TGF-ß/SMAD2/SMAD3. The PPB treatment significantly decreased its expression. In contrast, the HFD or oxLDL treatment significantly decreased the expression of the EC markers (PECAM-1 and vWF) while the PPB treatment significantly increased them. Moreover, the HFD or oxLDL treatment significantly increased the expression of the mesenchymal cell markers (α-SMA and vimentin) while PPB treatment significantly decreased them. PPB decreased the intima-media thickness and extracellular matrix amount of the aorta and attenuated the BP, which was increased by the HFD. In conclusion, PPB attenuated the upregulation of Lox-1/PKC-α/MMP9/TGF-ß/SMAD2 and 3 and restored the EndMT in HFD-fed animals. Moreover, PPB showed a restoring effect on HFD-induced hypertension.

Curcumin Mitigates Hypertension, Endothelial Dysfunction and Oxidative Stress in Rats with Chronic Exposure to Lead and Cadmium.

Lead (Pb) and cadmium (Cd) are environmental pollutants and nonessential elements in the body. Both metals induce the development of hypertension which is associated with oxidative stress. Curcumin (CUR) is a polyphenolic compound with strong antioxidant activity. The present study evaluated the effect of CUR on oxidative stress, alteration of vascular responsiveness and hypertension induced by exposure to either Pb, Cd or the combination of Pb and Cd. Male Sprague-Dawley rats were exposed to low level of lead acetate (100 mg/L) and/or cadmium chloride (10 mg/L) in the drinking water for 16 weeks. The control animals received deionized water as drinking water. CUR (100 mg/kg) or propylene glycol as vehicle was intragastrically administered once daily for the last 4 weeks. Exposure to Pb, Cd or the combination induced increases in blood pressure and peripheral vascular resistance, and decreased the blood pressure response to intravenous infusion to acetylcholine. Supplementation with CUR significantly reduced blood pressure, alleviated oxidative stress, and increased plasma nitrate/nitrite and glutathione in the blood. The effects of CUR were associated with the improvement of vascular responsiveness, upregulation of the endothelial nitric oxide synthase and downregulation of the NADPH oxidase expression. Furthermore, CUR reduced the metal levels in blood, aorta, liver and kidney. Altogether, exposure to the combination of Pb and Cd aggravated hypertension and oxidative stress, and CUR effectively ameliorated these adverse events in metal exposed animals. Data indicate that CUR may be useful as a dietary supplement for protection against the noxious effects of the heavy metals.

Tongmai Yangxin pill reduces myocardial No-reflow via endothelium-dependent NO-cGMP signaling by activation of the cAMP/PKA pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease. Previous studies have confirmed that TMYX can improve vascular endothelial function in patients with coronary heart disease by upregulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels. The underlying cAMP/PKA and NO-cGMP signaling pathway-dependent mechanism is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish the NR model. TMYX (4.0 g/kg) was orally administered throughout the experiment. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were used to evaluate the NR and ischemic areas. Pathological changes in the myocardium were assessed by hematoxylin-eosin staining. An automated biochemical analyzer and kit were used to detect the activities of myocardial enzymes and myocardial oxidants, including CK, CK-MB, LDH, reactive oxygen species, superoxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins related to the cAMP/PKA and NO/cGMP signaling pathways were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was used to detect coronary artery diastolic function in vitro. RESULTS: TMYX elevated the EF, FS, LVOT peak, LVPWd and LVPWs values, decreased the LVIDd, LVIDs, LV-mass, IVSd, and LV Vols values, demonstrating cardio-protective effects, and reduced the NR and ischemic areas. Pathological staining showed that TMYX could significantly reduce inflammatory cell number and interstitial edema. The activities of CK, LDH, and MDA were reduced, NO activity was increased, and oxidative stress was suppressed after treatment with TMYX. TMYX not only enhanced the expression of Gs-α, AC, PKA, and eNOS but also increased the expression of sGC and PKG. Furthermore, TMYX treatment significantly decreased ROCK expression. We further showed that TMYX (25-200 mg/mL) relaxed isolated coronary microvessels. CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the cAMP/PKA and NO/cGMP signaling pathways, further upregulating NO activity and relaxing coronary microvessels.

Anthocyanins attenuate vascular and inflammatory responses to a high fat high energy meal challenge in overweight older adults: A cross-over, randomized, double-blind clinical trial.

BACKGROUND & AIMS: Postprandial metabolic imbalances are important indicators of later developing cardiovascular disease (CVD). This study investigated the effects of food anthocyanins on vascular and microvascular function, and CVD associated biomarkers following a high fat high energy (HFHE) meal challenge in overweight older adults. METHODS: Sixteen subjects (13 female, 3 male, mean age 65.9 SD 6.0 and body mass index 30.6 kg/m2 SD 3.9) participated in a crossover, randomized, controlled, double-blind clinical trial (registered under Australian New Zealand Clinical Trials Registry, identifier no. ACTRN12620000437965). Participants consumed a HFHE meal with a 250 mL dose of either intervention (anthocyanins-rich Queen Garnet Plum) or control (apricot) juice. Blood samples and blood pressure measures were collected at baseline, 2 h and 4 h following the HFHE meal. Vascular and microvascular function were evaluated at baseline and 2 h after the HFHE meal. RESULTS: Participants had a higher 2 h postprandial flow-mediated dilatation (+1.14%) and a higher microvascular post-occlusive reactive hyperaemia (+0.10 perfusion units per mmHg) when allocated to the anthocyanin compared to the control arm (P = 0.019 and P = 0.049, respectively). C-reactive protein was lower 4 h postprandially in the anthocyanins (1.80 mg/L, IQR 0.90) vs control arm (2.30 mg/L, IQR 1.95) (P = 0.026), accompanied by a trend for lower concentrations of interleukin-6 (P = 0.075). No significant postprandial differences were observed between treatments for blood pressure, triacylglycerol, total cholesterol, serum derivatives of reactive oxidative metabolites, tumor necrosis factor alpha, interleukin-1 beta, or maximum microvascular perfusion following iontophoresis of acetylcholine. CONCLUSION: Fruit-based anthocyanins attenuated the potential postprandial detrimental effects of a HFHE challenge on parameters of vascular and microvascular function, and inflammatory biomarkers in overweight older adults. Anthocyanins may reduce cardiovascular risk associated with endothelial dysfunction and inflammatory responses to a typical high fat 'Western' meal. Further studies are required to better elucidate the clinical implications of postprandial biomarkers of CVD.

Identification of securinine as vascular protective agent targeting atherosclerosis in vascular endothelial cells, smooth muscle cells, and apolipoprotein E deficient mice.

BACKGROUND: Atherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue. PURPOSE: The purpose of the present study was to identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque. METHODS: Differentially expressed genes (DEGs) were analyzed in silico. The differentially expressed genes from 9 intimal thickening and 8 fibrous cap atheroma tissue which were collected from GEO data were assessed by the connectivity map. Natural candidate securinine, a main compound from Securinega suffruticosa, was selected and administrated 1, 5 mg/kg/day in apolipoprotein-E-deficient (ApoE KO) mice for 18 weeks. RESULTS: Securinine significantly showed lowered blood pressure and improvement of metabolic parameters with hyperlipidemia. The impairment in vasorelaxation was remarkably decreased by treatment with securinine. H&E staining revealed that treatment with securinine reduced atherosclerotic lesions. Securinine suppressed the expression of adhesion molecules and matrix metalloproteinase-2/-9 in both ApoE KO and vascular endothelial cells (HUVEC). In HUVEC pretreatment with securinine significantly inhibited ROS generation and NF-κB activation. Growth curve assays using the real-time cell analyzer showed that securinine significantly decreased TNF-α-induced aortic smooth muscle cell proliferation and migration in a dose-dependent manner. CONCLUSION: Securinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion.

Effect of pomegranate juice on vascular adhesion factors: A systematic review and meta-analysis.

BACKGROUND: Cardiovascular diseases, obesity, and insulin resistance demonstrate elements of functional impairment of the endothelium. Treatment of endothelial dysfunction with natural products, such as pomegranate, can open new ways in the treatment of cardiovascular diseases. PURPOSE: The present meta-analysis provides information in highlighting the role of pomegranate in endothelial dysfunction. METHODS: Various databases, such as PubMed, Scopus, Web of Science, Cochrane, and Google Scholar, were searched up to July 2020 using relevant keywords. We have selected the studies that investigated the effects of pomegranate on vascular adhesion factors, including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, and interleukin-6 (IL-6). MD with 95% CrI with 100,000 iterations by using Markov chain Monte Carlo code were used. RESULTS: Pooled effect size of articles in human studies indicated that pomegranate juice was not significantly effective on ICAM-1 [MD: -0.42; CrI: (-1.01, 0.17)], VCAM-1 [MD: -0.20; CrI: (-1.95, 1.40)], and E-selectin [MD: -0.21; CrI: (-1.62, 1.21)] compared to the control group. But it can significantly reduce IL-6 [MD: -1.07; CrI: (-1.90, -0.19)]. CONCLUSION: Generally, present study showed that pomegranate juice has no significant effect on vascular adhesion factors, ICAM-1, VCAM-1, and E-selectin, but can reduce IL-6 significantly. Future prospective randomized clinical trials with longer intervention duration are warranted to obtain a precise conclusion.

Physcion, a tetra-substituted 9,10-anthraquinone, prevents homocysteine-induced endothelial dysfunction by activating Ca2+- and Akt-eNOS-NO signaling pathways.

BACKGROUND: Homocysteine (Hcy) induced vascular endothelial dysfunction is known to be closely associated with oxidative stress and impaired NO system. 1,8-Dihydroxy-3-methoxy-6-methylanthracene-9,10-dione (physcion) has been known to has antioxidative and anti-inflammatory properties. PURPOSE: The purpose of the present study was to define the protective effect of physcion on Hcy-induced endothelial dysfunction and its mechanisms involved. STUDY DESIGN AND METHODS: Hyperhomocysteinemia (HHcy) rat model was induced by feeding 3% methionine. A rat thoracic aortic ring model was used to investigate the effects of physcion on Hcy-induced impairment of endothelium-dependent relaxation. Two doses, low (L, 30 mg/kg/day) and high (H, 50 mg/kg/day) of physcion were used in the present study. To construct Hcy-injured human umbilical vein endothelial cells (HUVECs) model, the cells treated with 3 mM Hcy. The effects of physcion on Hcy-induced HUVECs cytotoxicity and apoptosis were studied using MTT and flow cytometry. Confocal analysis was used to determine the levels of intracellular Ca2+. The levels of protein expression of the apoptosis-related markers Bcl-2, Bax, caspase-9/3, and Akt and endothelial nitric oxide synthase (eNOS) were evaluated by western blot. RESULTS: In the HHcy rat model, plasma levels of Hcy and malondialdehyde (MDA) were elevated (20.45 ± 2.42 vs. 4.67 ± 1.94 µM, 9.42 ± 0.48 vs. 3.47 ± 0.59 nM, p < 0.001 for both), whereas superoxide dismutase (SOD) and nitric oxide (NO) levels were decreased (77.11 ± 4.78 vs. 115.02 ± 5.63 U/ml, 44.51 ± 4.45 vs. 64.18 ± 5.34 µM, p < 0.001 and p < 0.01, respectively). However, treatment with physcion significantly reversed these changes (11.82 ± 2.02 vs. 20.45 ± 2.42 µM, 5.97 ± 0.72 vs. 9.42 ± 0.48 nM, 108.75 ± 5.65 vs. 77.11 ± 4.78 U/ml, 58.14 ± 6.02 vs. 44.51 ± 4.45 µM, p < 0.01 for all). Physcion also prevented Hcy-induced impairment of endothelium-dependent relaxation in HHcy rats (1.56 ± 0.06 vs. 15.44 ± 2.53 nM EC50 for ACh vasorelaxation, p < 0.05 vs. HHcy). In Hcy-injured HUVECs, physcion inhibited the impaired viability, apoptosis and reactive oxygen species. Hcy treatment significantly increased the protein phosphorylation levels of p38 (2.26 ± 0.20 vs. 1.00 ± 0.12, p <0.01), ERK (2.11 ± 0.21 vs. 1.00 ± 0.11, p <0.01) and JNK. Moreover, physcion reversed the Hcy-induced apoptosis related parameter changes such as decreased mitochondrial membrane potential (MMP) and Bcl-2/Bax protein ratio, and increased protein expression of caspase-9/3 in HUVECs. Furthermore, the downregulation of Ca2+, Akt, eNOS and NO caused by Hcy were recovered with physcion treatment in HUVECs. CONCLUSION: Physcion prevents Hcy-induced endothelial dysfunction by activating Ca2+- and Akt-eNOS-NO signaling pathways. This study provides the first evidence that physcion might be a candidate agent for the prevention of cardiovascular disease induced by Hcy.