TRPM7在细胞Mg~(2+)稳态调控中的作用及心血管生理学意义

Mg2+作为人体细胞内含量最多的二价阳离子,在人体生理活动中起着重要的作用。在心血管系统,Mg2+更是发挥着举足轻重的作用。已知与Mg2+相关的心血管疾病有动脉粥样硬化、高血压、心肌肥厚等。由于人体内Mg2+的跨膜转运机制仍不清楚,所以虽然已知这些疾病与Mg2+浓度的变化有相关性,但并不了解其具体的致病机制和治疗靶点。近年来国内外学者研究较多的Mg2+跨膜转运通道是TRP超家族通道,其中TRPM6和TRPM7两个成员被认为参与调控哺乳动物细胞内Mg2+平衡。该文就调节人体心血管系统内Mg2+平衡的重要通道——TRPM7通道与心血管系统之间的关系的研究进展做一简要综述。     

The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery.

The aliphatic amine aminoacetone has been described previously as a product of mitochondrial metabolism of threonine and glycine. Here, aminoacetone is shown to be deaminated to methylglyoxal by supernatants obtained by low speed centrifugation (600 g/10 min) of human umbilical artery homogenates, and also by membrane fractions isolated by high speed centrifugation (105,000 g/60 min) of these supernatants. Metabolism of 100 microM aminoacetone was completely inhibited by 1 mM propargylamine and MDL 72145, drugs which are capable of inhibiting the membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity found in vascular smooth muscle cells, whereas 1 mM pargyline and deprenyl which are inhibitors of monoamine oxidase, were without inhibitory effect. Estimated kinetic constants (at pH 7.8) for aminoacetone metabolism were Km = 92 microM; Vmax = 270 nmol/hr/mg protein. In addition, aminoacetone was a competitive inhibitor (Ki = 83 microM and 128 microM in low speed supernatants and high speed membrane fractions, respectively) of [14C]benzylamine metabolism by SSAO in this tissue. Aminoacetone would appear to be an endogenously occurring amine with a Km for metabolism by SSAO far lower than other aliphatic and aromatic biogenic amines examined previously as potential physiological substrates for the human vascular enzyme and possible implications of this are discussed.     

Involvement of semicarbazide-sensitive amine oxidase in tresperimus metabolism in human and in rat.

The metabolism of tresperimus, a new immunosuppressive agent, was investigated in vivo and in vitro in rat and in human. Two metabolic pathways were identified at each side of the molecule with two deamination reactions on the spermidine moiety and hydrolysis of the amide bond leading to the liberation of guanidinohexylamine. As the major metabolic pathway of the drug seemed to be the oxidative deamination, the capacity of different amine oxidases to metabolize tresperimus was then tested using in vivo experiments in rat and in vitro studies in rat and human plasma. The increase of tresperimus plasma levels induced by the administration of hydralazine, an irreversible in vivo inhibitor of semicarbazide-sensitive amine oxidase (SSAO), reflected the major involvement of this enzyme in tresperimus metabolism. This result was confirmed in vitro in rat and human plasma by the use of semicarbazide, a specific SSAO inhibitor. As opposed to rat plasma, human plasma may be an interesting in vitro model to study the metabolism of a drug extensively metabolized by SSAO such as tresperimus. Indeed, SSAO activity was significantly higher in human plasma than in rat plasma. The second metabolic pathway of the drug, which only occurred in rat plasma, appeared thus as the major route of tresperimus metabolism in this biological matrix.     

Localization of monoamine oxidase A and B and semicarbazide-sensitive amine oxidase in human peripheral tissues

Monoamine oxidase (MAO) A and B and semicarbazide-sensitive amine oxidase (SSAO) localizations in peripheral human tissues were compared by immunohistochemistry. The primary antibodies used were mouse monoclonal anti-human MAO-A (6G11/E1) and anti-human MAO-B (3F12/G10/2E3) and a rabbit polyclonal anti-bovine SSAO antibody. Immunoreactivities of the samples, obtained from 6 routine autopsy cases, showed different distributions in the tissues studied (heart, lung, duodenum, liver, pancreas, spleen, thyroid gland, adrenal gland and kidney). The relative MAO-A, MAO-B and SSAO distributions indicated a widespread distribution of these enzymes in the human body that is characterized by a matching cellular pattern in only few tissues. These differences suggest that each amine oxidase may play a specific function in, at least some, peripheral tissues.     

Contribution of calcium dysregulation to impaired coronary artery contraction in Zucker diabetic fatty rats

Diabetic coronary artery injury is closely associated with Ca²⁺ dysregulation, although the underlying mechanism remains unclear. This study explored the role and mechanism of Ca²⁺ handling in coronary artery dysfunction in type 2 diabetic rats. Zucker diabetic fatty (ZDF) rats were used as the type 2 diabetes mellitus model. The contractility of coronary artery rings induced by KCl, CaCl₂, 5-HT and U46619 was significantly lower in ZDF rats than in Zucker lean rats. Vasoconstriction induced by 5-HT and U46619 was greatly inhibited by nifedipine. However, in the presence of 1 μM nifedipine or in the Ca²⁺-free KH solution containing 1 μM nifedipine, there was no difference in the vasoconstriction between Zucker lean and ZDF rats. Store-operated calcium channels (SOCs) were not involved in coronary vasoconstriction. The downregulation of contractile proteins and the upregulation of synthesized proteins were in coronary artery smooth muscle cells (CASMCs) from ZDF rats. Metformin reversed the reduction of vasoconstriction in ZDF rats. Taken together, L-type calcium channel is important for regulating the excitation–contraction coupling of VSMCs in coronary arteries, and dysregulation of this channel contributes to the decreased contractility of coronary arteries in T2DM.     

The role of plasma semicarbazide-sensitive amine oxidase in allylamine and beta-aminopropionitrile cardiovascular toxicity: mechanisms of myocardial protection and aortic medial injury in rats

Allylamine (AA; 3-aminopropene) and beta-aminopropionitrile (betaAPN) combined treatment (AA + betaAPN) results in myocardial protection from AA-induced subendocardial necrosis and a rapid and extensive aortic medial smooth muscle injury in rats. To determine the mechanisms of AA + betaAPN-induced vascular toxicity, cardiovascular parameters were monitored during a 10-day exposure by gavage in male Sprague-Dawley rats (180-200 g). Water intake and urine output were measured in rats treated with water, AA (100 mg kg(-1) body weight), betaAPN (1 g kg(-1) body weight), and AA + betaAPN for 10 days in metabolic cages. Plasma and urine samples were analyzed for blood urea nitrogen, CO2, creatinine, hematocrit, electrolytes (Na+, K+, Cl-), and osmolality. Heart and plasma semicarbazide-sensitive amine oxidase metabolic capacity (SSAO)was also measured following 1, 3 and 10 days of treatment. Following 10 day exposure to control or AA + betaAPN treatment, thoracic aortic rings (approximately 3 mm) were removed, and aortic reactivity to contractile and relaxant agonists was tested in vitro. In addition, cultured rat aorta vascular smooth muscle cells or rat heart beating myocytes were exposed to various concentrations of AA and betaAPN or AA metabolites and betaAPN to test for synergism in vitro. Several of the changes in in vivo cardiovascular parameters were shared, both in direction and magnitude, between the AA + betaAPN and the AA alone or the betaAPN alone treatments. This suggests that these effects (e.g. increased water intake and urine flow, decreased hematocrit, decreased heart and plasma SSAO metabolic capacity) were dependent on an AA alone or a betaAPN alone effect and were not AA + betaAPN specific effects. Significant inhibition of plasma and heart SSAO metabolic capacity occurred in the betaAPN alone and the AA + betaAPN treatments, but not in the AA alone treatment. Aortic rings from AA + betaAPN treated rats were contracted significantly less than anatomically-matched control rat aortic rings by 100 mM potassium chloride or by 10 microM norepinephrine. BetaAPN offered substantial protection against AA cytotoxicity in cultured vascular smooth muscle cells and beating myocytes, but did not alter the cytotoxicity of AA metabolites (i.e. acrolein, H2O2, or ammonia) in vascular smooth muscle cells as determined by the MTT viability assay. Overall, these data suggest that myocardial protection from AA injury that occurs in the combined AA + betaAPN treatment is likely due to inhibition of plasma SSAO. This may result in an increase in the AA dose accumulation and metabolism in the aorta leading to the severe aortic medial injury.     

Effects of a Chinese herbal preparation on vascular cells in culture: mechanisms of cardiovascular protection

1. The use of traditional Chinese medicinal herbs or their pharmaceutical products for disease prevention and management is becoming increasingly popular in Western countries. Mixtures of various Chinese herbs have been used for the treatment of syndromes clinically overlapping Western cardiovascular syndromes. One modern preparation, known as the 'Cardiotonic Pill' (CP), is a pharmaceutical product derived mainly from a medicinal herb, Salvia miltiorrhiza bunge, and recently widely used in Chinese hospitals for the prevention and management of ischaemic cardiovascular diseases. Although the CP is believed to confer an extensive range of benefits, little is known about the physiological actions of this medicine, particularly at the cellular and molecular levels. Therefore, the aim of the present study was to explore possible cellular mechanisms of the CP on the cardiovascular system. 2. Cultured human vascular endothelial cells (EC) and vascular smooth muscle cells (VSMC) were exposed to the CP at various concentrations for periods ranging from hours to days. Cellular DNA synthesis was determined by a [(3)H]-thymidine incorporation assay, proliferation and death were assessed by investigations of cell numbers and apoptosis, whereas the expression of extracellular adhesion molecules was analysed by flow-cytometry and Western blotting. 3. The CP extract at concentrations of less than 200 microg/mL was not associated with cell damage. At doses beyond the therapeutic range (10-20 microg/mL), the CP appeared to exert a mild inhibitory effect on DNA synthesis and proliferation of EC in serum-enriched cultures. The CP significantly attenuated tumour necrosis factor-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in a dose-dependent manner, with 50 and 100 microg/mL CP producing decreases in the expression of ICAM-1 of 26-32% and 32-44%, respectively, and of VCAM-1 of approximately 23% and 27-42%, respectively. The CP did not affect apoptosis in EC under conditions of serum-deprivation. 4. In VSMC, the CP significantly inhibited platelet-derived growth factor BB-induced DNA synthesis and cell proliferation in a dose-dependent manner. The CP did not affect VSMC expression of adhesion molecules. 5. We conclude that the CP inhibits expression of ICAM-1 and VCAM-1 in EC and proliferation of VSMC in a manner that has potentially beneficial therapeutic effects.     

Effects of chronic monoamine oxidase inhibitor treatment on biogenic amine metabolism in rat brain.

The effects of acute and chronic administration of phenelzine and tranylcypromine on rat brain monoamine metabolism have been examined. Peak increases in norepinephrine, dopamine and 5-hydroxytryptamine occurred between 1 and 7 days with monoamine oxidase inhibitor treatments followed by a gradual decline in brain monoamines towards control levels with continued chronic drug administration. There was an associated adaptive increase in tryptophan hydroxylase but no change in tyrosine hydroxylase activity with chronic phenelzine treatment. Tranylcypromine did not affect tryptophan hydroxylase or tyrosine hydroxylase activities but was associated with a significant increase in aromatic amino acid decarboxylase activity after 14 and 21 days of treatment.     

咪达普利、缬沙坦抑制动脉粥样硬化的作用及机制

目的研究咪达普利，缬沙坦抑制动脉粥样硬化的作用及其机制。方法40只纯种大白兔随机分为4组。喂养8周后测定各组血清中总胴固醇（TC）、甘油三酯（TG）及低密度脂蛋白胆固醇（LDL），免疫组化观察粥样硬化斑块中STAT3、P21、CDK4的表达情况。结果高脂组、药物干预组血清TC、TG、LDL—C水平较对照组显著升高。STAT3、CDK4在药物干预组中表达较高脂组明显减少．而P21在药物干预组的表达较高脂组则明显升高。结论咪达普利、缬沙坦可明显抑制动脉粥样硬化的发生，其机制可能与抑制STAT3的信号传导和平滑肌增值有关。     

Anti-atherosclerotic effect of geniposidic acid in a rabbit model and related cellular mechanisms

Abstract

Context: Geniposidic acid, one of the main active ingredients in Gardenia jasminoides J. Ellis (Rubiaceae), may also possess important pharmacological activities for cardiovascular disorders similar to other derivatives, such as geniposide.

Objective: To evaluate its anti-atherosclerosis (anti-AS) effect, the related pharmacological activities and possible cellular mechanisms were studied.

Materials and methods: Thirty rabbits were randomly divided into normal control group, model control group, and geniposidic acid subgroups. In the AS model, its effects on the intima/media thickness ratio and aortic morphology were observed. In the study of primary cultured endothelial cells (ECs) and human umbilical artery smooth muscle cells (HUASMCs), its activities on both ECs and HUASMCs proliferation, HUASMCs' migration were also studied.

Results: Compared with the model control group, the plaque area, intima/media thickness ratio, and intimal foam cells number in geniposidic acid (80, 160, and 240?mg/kg) subgroups were significantly improved (p?<?0.05). By HE staining, the activities of geniposidic acid on relieving ECs shedding and improving aortic morphology disorders were also demonstrated. From the results of CCK-8 testing, only 100?μg/ml geniposidic acid performed significant inhibition on SMC proliferation. The relative IC₅₀ of geniposidic acid on SMC inhibition was 87.73?μg/ml. Geniposide acid also showed promotion effect on ECs proliferation, and the related ED₅₀ of geniposidic acid was 86.05?μg/ml. Besides, only 50 and 100?μg/ml geniposidic acid showed obvious inhibition on SMC migration from the upper chamber (p?<?0.05).

Discussion and conclusion: The effects of geniposidic acid on protecting vascular endothelium and reversing plaque formation in an atherosclerotic model were demonstrated.     

Subchronic toxicity of ethylene glycol in Wistar and F-344 rats related to metabolism and clearance of metabolites.

Ethylene glycol (CAS RN 107-21-1) can cause kidney toxicity via the formation of calcium oxalate crystals in a variety of species, including humans. Numerous repeated dose studies conducted in rats have indicated that male rats are more susceptible than female rats. Furthermore, subchronic and chronic studies using different dietary exposure regimens have indicated that male Wistar rats may be more sensitive to renal toxicity than male Fischer-344 (F-344) rats. This study was conducted to compare the toxicity of ethylene glycol in the two strains of rats under identical exposure conditions and to evaluate the potential contribution of toxicokinetic differences to strain sensitivity. Ethylene glycol was mixed in the diet at concentrations to deliver constant target dosage levels of 0, 50, 150, 500, or 1000 mg/kg/day for 16 weeks to groups of 10 male Wistar and 10 male F-344 rats based on weekly group mean body weights and feed consumption. Kidneys were examined histologically for calcium oxalate crystals and pathology. Samples of blood, urine, and kidneys from satellite animals exposed to 0, 150, 500, or 1000 mg/kg/day for 1 or 16 weeks were analyzed for ethylene glycol, glycolic acid, and oxalic acid. Treatment of Wistar rats at 1000 mg/kg/day resulted in the death of two rats; in addition, at 500 and 1000 mg/kg/day, group mean body weights were decreased compared to control throughout the 16 weeks. In F-344 rats exposed at 1000 mg/kg/day and in Wistar rats receiving 500 and 1000 mg/kg/day, there were lower urine specific gravities, higher urine volumes, and increased absolute and relative kidney weights. In both strains of rats treated at 500 and 1000 mg/kg/day, some or all treated animals had increased calcium oxalate crystals in the kidney tubules and crystal nephropathy. The effect was more severe in Wistar rats than in F-344 rats. Accumulation of oxalic acid in the kidneys of both strains of rats was consistent with the dose-dependent and strain-dependent toxicity. As the nephrotoxicity progressed over the 16 weeks, the clearance of ethylene glycol and its metabolites decreased, exacerbating the toxicity. Benchmark dose analysis indicated a BMDL05 for kidney toxicity in Wistar rats of 71.5 mg/kg/day; nearly fourfold lower than in F-344 rats (285 mg/kg/day). This study confirms that the Wistar rat is more sensitive to ethylene glycol-induced renal toxicity than the F-344 rat and indicates that metabolism or clearance plays a role in the strain differences.     

Transfection Efficiency and Cytotoxicity of Nonviral Gene Transfer Reagents in Human Smooth Muscle and Endothelial Cells

PURPOSE: Evaluation of a nonviral transfection reagent with respect to efficient gene transfer into primary human vascular cells. METHODS: Complexes consisting of seven commercially available transfection reagents (DAC-30, DC-30, Lipofectin, LipofectAMINE PLUS, Effectene, FuGene 6 and Superfect) and EGFP encoding plasmid DNA were studied. The in vitro transfection efficiency and cytotoxicity in human aorta smooth muscle cells (HASMCs) and endothelial cells (HAECs) and rat smooth muscle cells (A-10 SMCs) were assayed in the presence of serum using flow cytometric analysis and ATP-quantitation assay, respectively. RESULTS: Human primary cells were transfected less efficiently compared to the rat smooth muscle cell line. Transfection efficiency depended on the type of reagent, the reagent/DNA ratio, and, most importantly, on the cell type used. Determination of cytotoxicity showed that the effects of transfection on cell viability did not significantly differ from one another depending on the cell type. The exception to this was Superfect, which obviously reduced cell viability in all cell types. CONCLUSIONS: Our experiments showed that DAC-30 is the preferred transfection reagent for HASMCs and HAECs, exhibiting an improved efficiency combined with an acceptable cytotoxicity. Therefore, it might offer a therapeutic option for the treatment of cardiovascular disease and prove suitable for further drug development.     

The role of ATP-sensitive potassium channels in cellular function and protection in the cardiovascular system

ATP-sensitive potassium channels (K_ATP) are widely distributed and present in a number of tissues including muscle, pancreatic beta cells and the brain. Their activity is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels. Thus, they link cellular metabolism with membrane excitability. Recent studies using genetically modified mice and genomic studies in patients have implicated K_ATP channels in a number of physiological and pathological processes. In this review, we focus on their role in cellular function and protection particularly in the cardiovascular system.     

Effect of temperature on muscarinic cholinoceptor-mediated phosphoinositide metabolism and tension generation in bovine tracheal smooth muscle

The effect of decreased temperature on phosphoinositide metabolism was studied in flurbiprofen pretreated bovine tracheal smooth muscle (BTSM) by investigating the consequences of cooling on muscarinic-cholinoceptor-mediated [³H]inositol phosphate ([³H]InsP) and inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃) accumulation, basal phosphoinositidase C (PIC) activity and airways smooth muscle (ASM) tone. Cooling of [³H]Ins labelled BTSM slices from 37°C to 27°C for 20 min prior to the addition of agonist caused a substantial (73.0±2.5%) inhibition of carbachol (100 M, 30 min)-stimulated [³H]InsP accumulation compared to values measured at 37°C. The degree of inhibition of [³H]InsP accumulation was similar at all agonist time points (2–30 min) studied. In parallel experiments, cooling of unlabelled BTSM slices from 37°C to 27°C resulted in a 34% reduction in basal Ins(1,4,5)P₃ mass (37°C, 13.1±0.6 pmol mg^– protein; 27°C, 8.9±0.9 pmol mg^–1 protein; P<0.02) and markedly attenuated carbachol (100 M)-stimulated increases in Ins(1,4,5)P₃ accumulation. Basal PIC activity in the soluble fraction of BTSM homogenates, measured using a [³H]phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) /deoxycholate assay system, was also significantly lower at 27°C compared to 37°C (initial velocities of PtdIns(4,5)P₂ hydrolysis of 853±167 (37°C) and 418±119 (27°C) pmol min^–1 ml^–1 (1/400 diluted) BTSM cytosol; p<0.02). Cooling of BTSM strips from 37°C to 27°C for 20 min affected neither the lag period prior to the onset of contraction, the rate of force development, nor the final magnitude of the tension generated by carbachol (100 M). However, a significant attenuation of the contractile response by cooling to 27°C was observed using a submaximal (EC₂₀) concentration of carbachol. Also, the contractile response to 1 mM McN-A-343, a partial agonist at M₃-cholinoceptors was significantly attenuated at 27°C with mean increases in the lag time and the t_1/2 to achieve maximal contraction of 558% and 369% respectively and a mean decrease in the maximum force generated of 37%. Despite previous reports indicating that cooling can enhance agonist-stimulated [³H]InsP₃ accumulation in certain tissues, modest degrees of cooling clearly inhibit basal and carbachol-stimulated phosphoinositide hydrolysis in bovine tracheal smooth muscle and reduces the muscarinic receptor reserve in tracheal smooth muscle contraction.     

普伐他汀对溶血磷脂酰胆碱促血管平滑肌细胞增殖及细胞粘附的影响

目的　探讨羟甲基戊二酰辅酶A还原酶抑制剂普伐他汀对溶血磷脂酰胆碱 (LPC)促血管平滑肌细胞增殖及白细胞与内皮细胞粘附的影响。方法　用MTT法检测LPC对平滑肌细胞增殖的量效和时效关系及普伐他汀对LPC促平滑肌细胞增殖的影响 ;用直接记数法检测LPC诱导中性粒细胞系K5 6 2细胞与人脐静脉内皮细胞系ECV30 4细胞的粘附和普伐他汀对LPC所致白细胞与内皮细胞粘附的影响。结果　用 1～ 10 μmol·L-1LPC孵育血管平滑肌细胞 2 4～ 4 8h后 ,呈时间和剂量依赖性地诱导细胞增殖 ,而用 0 3～ 1mmol·L-1普伐他汀预孵育平滑肌细胞 1h ,再与 3μmol·L-1LPC共孵育 2 4～ 4 8h ,明显地抑制LPC所诱导的细胞增殖 ;用 3μmol·L-1LPC孵育ECV30 4细胞 12h显著增加K5 6 2细胞与ECV30 4细胞的粘附 ,而将ECV30 4细胞用 1mmol·L-1普伐他汀预处理后 ,明显减少白细胞与内皮细胞的粘附。结论　普伐他汀可抑制LPC促血管平滑肌细胞增殖及白细胞与内皮细胞粘附的作用。     

拉马克啉对内皮素-1诱导的大鼠血管平滑肌细胞增殖及蛋白激酶C表达的作用

目的：探讨拉马克啉（levcromakalim）对内皮素-1（ET-1）诱导的大鼠血管平滑肌细胞增殖及蛋白激酶C（protein kinase C，PKC）表达的影响。方法：体外培养Wistar大鼠主动脉血管平滑肌细胞（vascular smooth muscle cell，VSMCs），用ET-1诱导其增殖，用不同浓度拉马克啉共培养，MTT法评价VSMCs增殖情况，3H—TdR检测DNA合成，流式细胞术检测VSMCs凋亡，逆转录聚合酶链式反应（RT-PCR），Western blot检测PKCamRNA及蛋白表达。结果：拉马克啉对ET-1所致VSMCs增殖有显著抑制作用，随浓度增加，其MTT活性细胞含量和3H—TdR掺入量都明显减少（P〈0．05）；拉马克啉呈剂量依赖性地增加G0／G1期VSMCs（P〈0．05），促使VSMCs凋亡增多（P〈0．05）；拉马克啉抑制VSMCs内PKCamRNA及蛋白表达。结论：拉马克啉抑制ET-1诱导的VSMCs增殖作用，可能的机制是通过下调VSMCs内PKCa表达水平而影响vSMCs增殖和凋亡。     

熊果酸和齐墩果酸的血管药理作用研究进展

熊果酸和齐墩果酸能对抗氧化型低密度脂蛋白（ox-LDL）、C-反应蛋白、非酶糖基化终产物、高糖、H₂O₂、脂多糖对血管内皮细胞的损伤,其血管药理作用是多方面的。熊果酸和齐墩果酸能抑制血管平滑肌细胞增殖,也能对抗血清、ox-LDL、高糖、瘦蛋白诱导血管平滑肌细胞增殖,从而产生血管保护作用和改善血管功能;减轻糖尿病大鼠的血管损伤,减轻球囊导管损伤引起的血管狭窄,抑制静脉桥移植后的血管壁炎症反应和血管外膜成纤维细胞增殖并防止血管狭窄,以及防止多种实验性动脉粥样硬化模型动物的血管狭窄;对血管内皮细胞有抑制增殖作用,也有对抗伤害因子抑制增殖或促进增殖的双向作用,因此对血管生成也有双向调控作用,能抑制角膜、糖尿病动物视网膜及肿瘤组织内的血管新生;还有扩张血管,降低血管阻力,对正常的和多种高血压动物有显著的降压作用。     

吡格列酮和罗格列酮对脂多糖诱导大鼠血管平滑肌细胞增殖的影响

目的:观察胰岛素增敏剂——噻唑烷二酮类(TZD)药物吡格列酮和罗格列酮对脂多糖(LPS)诱导的血管平滑肌细胞(VSMCs)异常增殖的影响。方法:组织块贴壁法培养大鼠胸主动脉血管平滑肌细胞;LPS(0.1,1,10mg·L-1)干预血管平滑肌细胞不同时间(0,12,24,48,72h)后,分别用吡格列酮和罗格列酮与10mg·L-1LPS共同孵育72h,四甲基偶氮咗盐微量酶比色(MTT)法检测血管平滑肌细胞增殖。结果:10mg·L-1LPS孵育72h导致血管平滑肌细胞增殖程度最明显(P<0.01);吡格列酮和罗格列酮可明显抑制LPS诱导的血管平滑肌细胞增殖。结论:噻唑烷二酮类代表药吡格列酮和罗格列酮均对LPS诱导的血管平滑肌细胞异常增殖具有抑制作用,该类药物可能在治疗心血管疾病方面有较好的应用前景。     

Pharmacology in health food: metabolism of quercetin in vivo and its protective effect against arteriosclerosis

Quercetin, a member of the bioflavonoids family, has been proposed to have anti-atherogenic, anti-inflammatory, and anti-hypertensive properties leading to the beneficial effects against cardiovascular diseases. It was recently demonstrated that quercetin 3-O-β-D-glucuronide (Q3GA) is one of the major quercetin conjugates in human plasma, in which the aglycone could not be detected. Although most of the in vitro pharmacological studies have been carried out using only the quercetin aglycone form, experiments using Q3GA would be important to discover the preventive mechanisms of cardiovascular diseases by quercetin in vivo. Therefore we examined the effects of the chemically synthesized Q3GA, as an in vivo form, on vascular smooth muscle cell (VSMC) disorders related to the progression of arteriosclerosis. Platelet-derived growth factor-induced cell migration and proliferation were inhibited by Q3GA in VSMCs. Q3GA attenuated angiotensin II-induced VSMC hypertrophy via its inhibitory effect on JNK and the AP-1 signaling pathway. Q3GA scavenged 1,1-diphenyl-2-picrylhydrazyl radical measured by the electron paramagnetic resonance method. In addition, immunohistochemical studies with monoclonal antibody 14A2 targeting the Q3GA demonstrated that the positive staining specifically accumulates in human atherosclerotic lesions, but not in the normal aorta. These findings suggest Q3GA would be an active metabolite of quercetin in plasma and may have preventative effects on arteriosclerosis relevant to VSMC disorders.