Hypoglycaemic and Antioxidant Properties of Acrocomia aculeata (Jacq.) Lodd Ex Mart. Extract Are Associated with Better Vascular Function of Type 2 Diabetic Rats.

Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2). Acrocomia aculeata (Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto-Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg-1 aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H2O2. EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications.

Effect of Vitamin D Status on Vascular Function of the Aorta in a Rat Model of PCOS.

Polycystic ovary syndrome (PCOS) is associated with elevated cardiovascular risk. Early vascular dysfunction may lead to the development of cardiovascular disease in PCOS. Vitamin D deficiency (VDD) is a common comorbidity of PCOS that contributes to the pathogenesis of the disease and its complications. Both PCOS and VDD are accompanied by increased oxidative stress that may be involved in the arising vascular dysfunction. We aimed to investigate the role of vitamin D status on aortic function. PCOS was induced by an 8-week-long transdermal testosterone treatment of female rats, and low and adequate vitamin D status was achieved by dietary means. Contraction and relaxation abilities of isolated aortic segments were measured by myograph. Resorcin-fuchsin staining and immunohistochemical labeling of 3-nitrotyrosine were performed. No difference was shown in the norepinephrine-induced contraction of the aortas of different groups, whereas we detected reduced acetylcholine- and insulin-evoked relaxation in VDD groups. A lower level of resorcin-fuchsin staining and elevated 3-nitrotyrosine immunostaining was observed in VDD. In our study, we demonstrated early endothelial dysfunction in VDD PCOS rat model. Vitamin D supplementation could prevent vascular disturbances, while VDD itself damaged endothelium-dependent vasorelaxation and induced nitrative stress.

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.

Polydatin alleviates high-fat diet induced atherosclerosis in apolipoprotein E-deficient mice by autophagic restoration.

BACKGROUND: Polydatin has been reported to possess remarkable anti-atherosclerotic activities. However, there are different opinions on its regulatory mechanisms. It remains unclear whether the anti-atherosclerotic mechanism of polydatin is related to its autophagic restoration or not. The aim of this study was to explore the question. METHODS: Using atherosclerotic model induced by high-fat diet in apolipoprotein E-deficient mice, the investigation was performed with polydatin alone or in combination with autophagic inhibitor or inducer intervention. Inhibitory sites of polydatin to PI3K were identified by molecular docking. RESULTS: Polydatin can significantly inhibit PI3K/Akt/mTOR pathway proteins expression, improve autophagic dysfunction and reduce atherosclerotic lesions. These effects could be antagonized and reinforced by adding autophagic inhibitor and inducer, respectively. Inhibitory sites of polydatin to PI3K were found to be ASP-810, SER-854, VAL-851, LEU-807, SER-774, LYS-802, ASP-933, SER-919, ASN-920, PHE-930, MEF-922, GLN-859 of PI3Kα. CONCLUSIONS: The mechanism of polydatin to alleviate atherosclerotic lesions was achieved by autophagic restoration.

Experimental model of congestive heart failure induced by transverse aortic constriction in BALB/c mice.

INTRODUCTION: Murine transverse aortic constriction (TAC) is a frequently used model of pressure overload-induced left ventricular (LV) remodeling. However, there is considerable variability in disease progression to overt heart failure (HF) development in the most commonly used strain of mice (i.e., C57BL/6J). Studies have shown that C57BL/6J mice are more resistant than BALB/c mice to congestive HF development following myocardial infarction or angiotensin II-induced hypertension. Therefore, we tested the hypothesis that BALB/c mice may be a better research model to study TAC-induced progressive HF. METHODS: Following sham or TAC surgery in both C57BL/6J (n = 29) and BALB/c (n = 32) mice, we evaluated cardiac dimensions and function by echocardiography at 2, 4, 8, and 12 weeks and monitored survival throughout the study. In a separate cohort of BALB/c mice, we repeated the study in the presence of the angiotensin converting enzyme inhibitor enalapril or a vehicle initiated 2 weeks post-TAC and administered for 6 weeks. At the end of the studies, we assessed the heart weight, lung weight, and plasma brain natriuretic peptide (BNP) concentration. RESULTS: Following comparable TAC, both C57BL/6J and BALB/c mice showed significant LV remodeling compared with the sham control mice. BALB/c mice progressively developed systolic dysfunction, LV dilation, lung congestion, and significant mortality, whereas C57BL/6J mice did not. In the separate cohort of BALB/c TAC mice, enalapril significantly reduced the heart weight, lung weight, and plasma BNP concentration and improved survival compared with the vehicle control. DISCUSSION: BALB/c mice uniformly developed congestive HF post-TAC. Enalapril was effective in improving survival and reducing lung congestion in this model. The data suggest that BALB/c mice may be a better research tool than C57BL/6J mice to study TAC-induced disease progression to HF and to evaluate novel therapies for the treatment of chronic HF with reduced ejection fraction.

Vasorelaxant effects of 50 commonly used traditional herbal prescriptions on isolated rat aortic rings.

OBJECTIVE: To investigate the vasorelaxant activities of 50 common traditional herbal prescriptions (THPs) on isolated rat aortic rings. METHODS: An electric extractor was used to extract THPs. Rat aortic rings were precontracted using phenylephrine in organ chambers containing Krebs-Henseleit solution. Decoctions of THPs were added in increasing concentrations (10-1000 µg/mL) to investigate vasorelaxant activities. The vasorelaxant effects of THPs were calculated as percentage of contraction in response to phenylephrine. RESULTS: Several THPs such as Tianwangbuxin Dan, Banxiaxiexin Tang, and Mahuang Tang, significantly relaxed precontracted aortic rings. In contrast, Xiaochaihu Tang, Shensuyin, and Guizhifuling Wan significantly contracted aortic rings. Furthermore, these THPs increasingly relaxed or contracted aortic rings relaxed by amlodipine. CONCLUSION: Our findings suggest that hypertension can be treated using THPs. However some THPs can counteract treatment of hypertension. Further studies should be developed on use of THPs for treatment of hypertension are critical, and guidelines for use of traditional herbal medicines to treat hypertension.

Improvement of Endothelial Dysfunction of Berberine in Atherosclerotic Mice and Mechanism Exploring through TMT-Based Proteomics.

Atherosclerosis is a multifactorial vascular disease triggered by disordered lipid metabolism, characterized by chronic inflammatory injury, and initiated by endothelial dysfunction. Berberine is the main active alkaloid of the herbal medicine Coptidis Rhizoma (Huanglian). Notably, berberine has been shown to have beneficial effects against atherosclerosis. However, the mechanisms of berberine in preventing atherosclerosis are still unclear. This study is aimed at investigating the effects and mechanisms of berberine in protecting the aorta and ameliorating atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Here, we demonstrated that berberine reduced serum lipid levels, antagonized hepatic lipid accumulation, improved intima-media thickening, and alleviated atherosclerotic lesions in ApoE-/- mice fed a western-type diet for 12 weeks. Meanwhile, berberine reduced aortic reactive oxygen species (ROS) generation and reduced the serum levels of malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), and interleukin-6 (IL-6). In aortic ring assay, berberine restored aortic endothelium-dependent vasodilatation in vivo and in vitro. Furthermore, 4,956 proteins were identified by proteomic analysis, and 199 differentially expressed proteins regulated by berberine were found to be involved in many biological pathways, such as mitochondrial dysfunction, fatty acid ß-oxidation I, and FXR/RXR activation. Summarily, these data suggested that berberine ameliorates endothelial dysfunction and protects against atherosclerosis, and thus may be a promising therapeutic candidate for atherosclerosis.

Effects of Whey Protein Supplementation on Aortic Stiffness, Cerebral Blood Flow, and Cognitive Function in Community-Dwelling Older Adults: Findings from the ANCHORS A-WHEY Clinical Trial.

ANCHORS A-WHEY was a 12-week randomized controlled trial (RCT) designed to examine the effect of whey protein on large artery stiffness, cerebrovascular responses to cognitive activity and cognitive function in older adults. METHODS: 99 older adults (mean ± SD; age 67 ± 6 years, BMI 27.2 ± 4.7kg/m2, 45% female) were randomly assigned to 50g/daily of whey protein isolate (WPI) or an iso-caloric carbohydrate (CHO) control for 12 weeks (NCT01956994). Aortic stiffness was determined as carotid-femoral pulse wave velocity (cfPWV). Aortic hemodynamic load was assessed as the product of aortic systolic blood pressure and heart rate (Ao SBP × HR). Cerebrovascular response to cognitive activity was assessed as change in middle-cerebral artery (MCA) blood velocity pulsatility index (PI) during a cognitive perturbation (Stroop task). Cognitive function was assessed using a computerized neurocognitive battery. RESULTS: cfPWV increased slightly in CHO and significantly decreased in WPI (p < 0.05). Ao SBP × HR was unaltered in CHO but decreased significantly in WPI (p < 0.05). Although emotion recognition selectively improved with WPI (p < 0.05), WPI had no effect on other domains of cognitive function or MCA PI response to cognitive activity (p > 0.05 for all). CONCLUSIONS: Compared to CHO, WPI supplementation results in favorable reductions in aortic stiffness and aortic hemodynamic load with limited effects on cognitive function and cerebrovascular function in community-dwelling older adults.

The Seed Coat Extract of Black Soybean Decreases Nicotine-Induced Vascular Fiber Degradation by Suppressing Matrix Metalloproteinase 2 Expression.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by weakening of vascular walls and progressive dilation of the abdominal aorta. Nicotine, the main component of tobacco, is reportedly associated with the development and rupture of AAA. It is desirable to attenuate the destructive effect of nicotine on vascular walls, using dietary food components. However, effective methods for preventing AAA progression using dietary food components remain unestablished. This study focuses on proanthocyanidins, well known for their potent antioxidant activity. We speculated that proanthocyanidins can suppress nicotine-induced weakening of vascular walls. To estimate the effect of black soybean seed coat extract (BSSCE), rich in proanthocyanidins, on nicotine-induced weakening of the aortic wall, mice were divided into four groups: the control diet and distilled water group (named C), BSSCE solution diet and distilled water group (named B), control diet and 0.5 mg/mL nicotine solution group (named CN), and BSSCE solution diet and 0.5 mg/mL nicotine solution group (named BN). Nicotine-induced degradation of elastin and collagen fibers were significantly suppressed in BN group. The positive areas for matrix metalloproteinase (MMP)-2 and oxidative stress in BN group were significantly decreased compared to those in CN group. These results suggest that proanthocyanidins-rich BSSCE can prevent the weakening of the aortic wall via inhibiting MMP-2 upregulation.

Rooibos (Aspalathus linearis) protects against nicotineinduced vascular injury and oxidative stress in Wistar rats.

BACKGROUND: Rooibos (Aspalathus linearis) is an indigenous South African plant, traditionally used by the local population as a remedy against several ailments. More recently, rooibos was shown to exhibit potent antioxidant properties, attributed to its polyphenols. We assessed whether treatment with fermented rooibos (RF), unfermented rooibos (RUF) and melatonin (Mel), a well-documented antioxidant included for comparison, could counter the harmful vascular and pro-oxidant effects of nicotine. METHODS: Vascular function, antioxidant enzyme activity and lipid peroxidation were assessed in male adult rats treated with nicotine (5 mg/kg body weight/day) and 2% RF, 2% RUF or 4% Mel co-administration. Nitric oxide (NO) production and cell viability were measured in nicotine-exposed rat aortic endothelial cells (AECs) pre-treated with RF (0.015 mg/ml). RESULTS: Vascular studies showed that co-administration with RF or Mel exerted anti-contractile and pro-relaxation responses in aortic rings, and increased hepatic superoxide dismutase and catalase activity in nicotine-exposed animals. Co-treatment with Mel additionally decreased lipid peroxidation in nicotine-exposed rats. RUF exerted anti-contractile responses in aortic rings of nicotine-treated animals, while in nicotine-exposed AECs, RF pre-treatment increased intracellular NO levels. CONCLUSIONS: For the first time, we have shown that rooibos co-treatment exerted beneficial vascular effects in nicotine-exposed rats, and that this was associated with increased antioxidant enzyme activity.

Fast Isolation of Flavonoids from the Endemic Species Nolana ramosissima I.M. Johnst and Its Endothelium-Independent Relaxation Effect in Rat Aorta.

The infusion of the desertic plant Nolana ramosissima I.M. Johnst showed vascular smooth muscle relaxation in rat aorta and the presence of several phenolic compounds, which were detected by high resolution UHPLC-Orbitrap-HESI-MS. In addition, five flavonoids were rapidly isolated from a methanolic extract using high-performance counter-current chromatography (HPCCC). The N. ramosissima extract showed endothelium-independent relaxation effect in rat aorta. Sixty-one compounds were detected in the infusion, mainly glycosylated flavonoids, flavanones and several oxylipins, suggesting that a synergistic effect between the compounds in the extracts could be responsible for the relaxation activity. Vascular activity experiments were done in isolated organ bath. In rat aorta, a nitric oxide inhibitor did not prevent the relaxation effects of the extract; however, a selective guanylyl cyclase inhibitor partially blunted this effect. The compound 5,3'-dihydroxy-4'7-dimethoxyflavone presented higher relaxation effect than 100 µg/mL of N. ramosissima extract. The extract and the isolated metabolites from N. ramosissima can show relaxation effects on rat aorta by a mechanism that is independent of the endothelium.

Medial calcification in the arterial wall of smooth muscle cell-specific Smpd1 transgenic mice: A ceramide-mediated vasculopathy.

Arterial medial calcification (AMC) is associated with crystallization of hydroxyapatite in the extracellular matrix and arterial smooth muscle cells (SMCs) leading to reduced arterial compliance. The study was performed to test whether lysosomal acid sphingomyelinase (murine gene code: Smpd1)-derived ceramide contributes to the small extracellular vesicle (sEV) secretion from SMCs and consequently leads to AMC. In Smpd1trg /SMcre mice with SMC-specific overexpression of Smpd1 gene, a high dose of Vit D (500 000 IU/kg/d) resulted in increased aortic and coronary AMC, associated with augmented expression of RUNX2 and osteopontin in the coronary and aortic media compared with their littermates (Smpd1trg /SMwt and WT/WT mice), indicating phenotypic switch. However, amitriptyline, an acid sphingomyelinase (ASM) inhibitor, reduced calcification and reversed phenotypic switch. Smpd1trg /SMcre mice showed increased CD63, AnX2 and ALP levels in the arterial wall, accompanied by reduced co-localization of lysosome marker (Lamp-1) with multivesicular body (MVB) marker (VPS16), a parameter for lysosome-MVB interaction. All these changes related to lysosome fusion and sEV release were substantially attenuated by amitriptyline. Increased arterial stiffness and elastin disorganization were found in Smpd1trg /SMcre mice as compared to their littermates. In cultured coronary arterial SMCs (CASMCs) from Smpd1trg /SMcre mice, increased Pi concentrations led to markedly increased calcium deposition, phenotypic change and sEV secretion compared with WT CASMCs, accompanied by reduced lysosome-MVB interaction. However, amitriptyline prevented these changes in Pi -treated CASMCs. These data indicate that lysosomal ceramide plays a critical role in phenotype change and sEV release in SMCs, which may contribute to the arterial stiffness during the development of AMC.

Stachydrine hydrochloride alleviates pressure overload-induced heart failure and calcium mishandling on mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Leonurus japonicus Houtt. has a long history in the treatment of cardiovascular diseases. Stachydrine hydrochloride, the main bioactive ingredient extracted from Leonurus japonicus Houtt., has been shown to have cardioprotective effects. However, the underlying mechanisms of stachydrine hydrochloride haven't been comprehensively studied so far. AIM OF THE STUDY: The aim of this study was to investigate the protective role of stachydrine hydrochloride in heart failure and elucidate its possible mechanisms of action. MATERIALS AND METHODS: In vivo, transverse aorta constriction was carried out in C57BL/6J mice, and thereafter, 7.2 mg/kg telmisartan (a selective AT1R antagonist as positive control) and 12 mg/kg stachydrine hydrochloride was administered daily intragastrically for 4 weeks. Cardiac function was evaluated by assessing morphological changes as well as echocardiographic and haemodynamic parameters. In vitro, neonatal rat cardiomyocytes or adult mice cardiomyocytes were treated with stachydrine hydrochloride and challenged with phenylephrine (α-AR agonist). Ventricular myocytes were isolated from the hearts of C57BL/6J mice by Langendorff crossflow perfusion system. Intracellular calcium was measured by an ion imaging system. The length and movement of sarcomere were traced to evaluate the systolic and diastolic function of single myocardial cells. RESULTS: Stachydrine hydrochloride improved the cardiac function and calcium transient amplitudes, and inhibited the SR leakage and the amount of sparks in cardiac myocytes isolated from TAC mice. We also demonstrated that stachydrine hydrochloride could ameliorated phenylephrine-induced enhance in sarcomere contraction, calcium transients and calcium sparks. Moreover, our data shown that stachydrine hydrochloride blocked the hyper-phosphorylation of CaMKII, RyR2, PLN, and prevented the disassociation of FKBP12.6 from RyR2. CONCLUSION: Our results suggest that stachydrine hydrochloride exerts beneficial therapeutic effects against heart failure. These cardioprotective effects may be associated with the regulation of calcium handling by stachydrine hydrochloride through inhibiting the hyper-phosphorylation of CaMKII.

Hyperbaric oxygenation affects acetylcholine-induced relaxation in female diabetic rats.

We aimed to assess the effects of intermittent hyperbaric oxygenation (HBO2 at 2 bars for 120 minutes a day for four successive days) on acetylcholine-induced vasorelaxation (AChIR) in female Sprague-Dawley (SD) rats (N=80) that were randomized into four groups: healthy controls (CTR); diabetic rats (DM); and control and diabetic rats that underwent hyperbaric oxygenation (CTR+HBO and DM+HBO), respectively. AChIR was measured in vitro in aortic rings, with/without L-NAME, MS-PPOH, HET0016 or indomethacin. mRNA expression of eNOS, iNOS, COX-1, COX-2, thromboxane A synthase 1 (TBXAS1), CYP4A1, CYP4A3 and CYP2J3 was assessed by qPCR. Systemic oxidative stress and plasma antioxidative capacity were determined with the thiobarbituric acid-reactive substances (TBARS) and the ferric reducing ability of plasma (FRAP) assays, respectively. There was no significant difference in AChIR among experimental groups of rats. In CTR and DM group of rats, AChIR was mediated by NO and EETs pathway, while in the CTR+HBO and DM+HBO groups, NO-pathway prevailed. iNOS expression was upregulated in the DM group compared to CTR, while HBO2 upregulated eNOS in CTR group and TBXAS1 in DM group of rats. In both, CTR and DM group of rats, the sensitivity to ACh in the presence of L-NAME or in the presence of MSPPOH was significantly decreased compared to the response to ACh in the absence or presence of indomethacin or HET0016. DM and DM+HBO rats had increased TBARS compared to their respective controls. In conclusion, HBO2 presumably alters vasorelaxation in response to ACh from NO-EETs mediated pathways to solely NO-pathway, without affecting oxidative status of DM rats.

Mapping and Ablation of Arrhythmias from Uncommon Sites (Aortic Cusp, Pulmonary Artery, and Left Ventricular Summit).

Despite advances in our understanding of the relevant anatomy and mapping and catheter ablation techniques of idiopathic outflow tract ventricular arrhythmias, challenging sites for catheter ablation remain the aortic cusps, pulmonary artery, and notably the left ventricular summit. A systematic approach should be used to direct mapping efforts efficiently between endocardial, coronary venous, and epicardial sites. Foci at the left ventricular summit, particularly intraseptal and at the inaccessible epicardial region, remain difficult to reach and when percutaneous techniques fail, surgical ablation remains an option but with risk of late coronary artery stenosis.

Chronic Treatment with α-Lipoic Acid Improves Endothelium-Dependent Vasorelaxation of Aortas in High-Fat Diet-Fed Mice.

α-Lipoic acid (ALA) is used as a dietary supplement and known as an anti-oxidant. The present study aimed to examine whether ALA improves endothelial dysfunction in high-fat diet-fed obese mice. After feeding a high-fat diet to Institute of Cancer Research (ICR) mice for 4 weeks, the mice were maintained with a high-fat diet (group HF) or a high-fat diet containing ALA (25 mg/d, group HF + ALA) for an additional 20 weeks. Age-matched normal diet-fed mice were also used (group Normal). Chronic oral treatment with ALA did not affect various plasma parameters or body weights. As compared with the aortas of Normal mice, those from HF mice showed impaired endothelium-dependent relaxation in response to clonidine. However, such an impairment was not observed in the aortas from HF + ALA mice. The plasma levels of thiobarbituric acid reactive substances, an indicator of oxidative stress, were significantly decreased in HF + ALA mice compared with HF mice, confirming the anti-oxidative effects of ALA. In addition, when the impaired clonidine-induced vasorelaxation of aortas from normal mice under high glucose conditions was used as a model of acute oxidative stress, the vasorelaxation responses were improved in the presence of ALA at 100 µM. Our results suggested that the chronic oral administration of ALA improves endothelial dysfunction in high-fat diet-fed obese mice possibly through the reduction in oxidative stress in vivo.

Germacrane Sesquiterpenoids as a New Type of Anticardiac Fibrosis Agent Targeting Transforming Growth Factor ß Type I Receptor.

A germacrane sesquiterpenoid library containing 30 compounds (2-31) was constructed by structural modification of a major component aristolactone (1) from the traditional Chinese medicine Aristolochia yunnanensis. Compound 11 was identified as a promising anticardiac fibrosis agent by systematic screening of this library. 11 could inhibit the expression of fibronectin (FN), α-smooth muscle actin (α-SMA), and collagens in transforming growth factor ß 1 (TGFß1)-stimulated cardiac fibroblasts at a micromolar level and ameliorate myocardial fibrosis and heart function in abdominal aortic constriction (AAC) rats at 5 mg/kg dose. Mechanistic study revealed that 11 inhibited the TGFß/small mother against decapentaplegic (Smad) signaling pathway by targeting TGFß type I receptor (IC50 = 14.9 ± 1.6 nM). The structure-activity relationships (SARs) study indicated that the unsaturated γ-lactone ring and oxidation of C-1 were important to the activity. These findings may provide a new type of structural motif for future anticardiac fibrosis drug development.

Titrate to equilibrate and not exsanguinate! Characterization and validation of a novel partial resuscitative endovascular balloon occlusion of the aorta catheter in normal and hemorrhagic shock conditions.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a significant advancement in the control of noncompressible truncal hemorrhage. However, its ischemic burden and reperfusion injury following balloon deflation limits its utilization. Partial restoration of aortic flow during REBOA has the potential to balance hemorrhage control and ischemia. This study validates the mechanics, physiology, and optimal partial flow rates using a prototype partial REBOA (pREBOA) device. METHODS: Twenty-five swine underwent placement of aortic flow probes and zone 1 pREBOA. Experiment 1 (N = 5) animals were not injured and assessed the tested the catheters ability to titrate and control flow. Experiment 2 (N = 10) added 20% hemorrhage and either solid organ, or abdominal vascular injury to compare flow rate and rebleeding from injuries. Experiment 3 (N = 10) swine were similarly prepared, hemorrhaged, and underwent pREBOA at set partial flow rates for 2 hours followed by complete deflation for 30 minutes. RESULTS: Balloon volume at minimum flow (mean, 0.09 L/min) was 3.5 mL to 6.0 mL. Half maximal flow was achieved with 56.5% of maximum balloon inflation. Partial REBOA allowed very fine titration of flow rates. Rebleeding occurred at 0.45 L/min to 0.83 L/min. Distal flow of 0.7 L/min had 50% survival, 0.5 had 100% survival, and 0.3 L had 50% survival with mean end lactates of 9.6, 12.6, and 13.3, respectively. There was a trend toward hyperkalemia and hypocalcemia in nonsurvivors. CONCLUSION: The pREBOA device demonstrated a high level of titratability for restoration of aortic flow. An optimal partial flow of 0.5 L/min was effective at hemorrhage control while limiting the burden of ischemic injury, and extending the tolerable duration of zone 1 occlusion. Aggressive calcium supplementation prior to and during partial occlusion and reperfusion may be warranted to prevent hyperkalemic arrest.

Molecular evidence of tissue remodeling in an animal model of heart failure.

Heart failure (HF) is the final common pathway of many cardiovascular diseases. Metalloproteinases and their inhibitors, such as MMP9 and TIMP-1, assist in maintaining the extracellular matrix, leading to tissue remodeling observed after HF. Previous studies have shown that L-Arginine (LA) appears to have beneficial effects for the treatment of HF, contributing to vasodilation, the reestablishment of the endothelial function and an increase in muscle contractile force. This study analyzed heart tissue remodeling in an animal model of HF induced by aortocaval fistula (ACF) and submitted to LA treatment. After 4 weeks of ACF, animals were treated with LA for 4 weeks (SHAM-LA, HF-LA) or for 8-12 weeks with saline (SHAM, HF8, HF12). Rats were euthanized and the hearts removed for histological processing. The samples were stained with Hematoxylin-Eosin (HE), Masson's Thichome (MT), or submitted to immunohistochemistry (IHC) for MMP9 and TIMP-1. Light microscopy analysis showed cardiac striated muscle without fibrosis in all experimental groups. Immunostaining of MMP9 and TIMP-1 were positive for all experimental groups. LA administration significatively reduced MMP9 content after HF. These data indicate molecular changes in metalloproteinases expression prior to tissue remodeling and point out LA as an adjuvant therapy to pharmacological treatment of patients with HF.