Selected Zinc Metabolism Parameters and Left Ventricle Mass in Echocardiographic Examination in Primary Arterial Hypertension

The basal systolic and diastolic blood pressure, body mass index, left ventricular mass, serum and lymphocyte zinc levels, serum aldosterone, plasma rennin and angiotensin-converting enzyme activities, sodium and potassium levels, and the total and ouabain-dependent rate constants of zinc efflux from lymphocytes were measured in a group of 41 individuals of both sexes (overall age 46.3 ± 11.4 years), of which 18 were women (48.5 ± 7.1 years old) and 23 were men (44.7 ± 13.8 years old). There were no significant differences between these parameters while dividing the subjects into groups according to sex, despite differences in weight, left ventricle mass, plasma rennin activity, and serum aldosterone content. Only the total and ouabain-dependent rate constants of zinc efflux from lymphocytes slightly negatively correlated to left ventricular mass, r = −0.30 to r = −0.36. This may constitute indirect evidence of zinc deficiency in cardiomyocytes of some hypertensive individuals with left ventricular hypertrophy.     

Role of zinc in regulation of arterial blood pressure and in the etiopathogenesis of arterial hypertension

Increased gastrointestinal absorption and urinary excretion of zinc has been confirmed in experimental and clinical studies on primary arterial hypertension as a result from changes of intracellular and extracellular zinc content. In arterial hypertension, the levels of zinc in serum, lymphocyte, and bone decrease while increasing in heart, erythrocytes, kidney, liver, suprarenal glands and spleen. These changes result in the loss of zinc homeostasis that leads to various degrees of deficiency, not entirely compensated by nutritional factors or increased absorption in the gastrointestinal tract. Loss of zinc homeostasis can be both cause and effect of high blood pressure. In the present review, the role of zinc metabolism changes and its mechanisms in arterial hypertension are discussed.     

Role of PI3K and PKB/Akt in acute natriuretic and NO-mimetic effects of leptin

Apart from controlling energy balance, leptin, a peptide hormone secreted by white adipose tissue, is also involved in the regulation of cardiovascular function. Previous studies have documented that leptin stimulates natriuresis and nitric oxide (NO) production, but the mechanism of these effects is incompletely elucidated. We examined whether phosphoinositide 3-kinase (PI3K) and its downstream effector, protein kinase B/Akt are involved in acute natriuretic and NO-mimetic effects of leptin in anaesthetized rats. Leptin (1 mg/kg i.v.) induced a marked increase in natriuresis and this effect was abolished by pretreatment with either wortmannin (15 μg/kg) or LY294002 (0.6 mg/kg), two structurally different PI3K inhibitors. Moreover, leptin increased plasma concentration and urinary excretion of NO metabolites, nitrites + nitrates (NO_x), and of NO second messenger, cyclic GMP. In addition, leptin increased NO_x and cGMP in aortic tissue. The stimulatory effect of leptin on NO_x and cGMP was prevented by PKB/Akt inhibitor, triciribine, but not by either wortmannin or LY294002. Triciribine had no effect on leptin-induced natriuresis. Leptin stimulated Akt phosphorylation at Ser⁴⁷³ in aortic tissue but not in the kidney. These results suggest that leptin-induced natriuresis is mediated by PI3K but not Akt, whereas NO-mimetic effect of leptin results from PI3K-independent stimulation of Akt.     

Cardiovascular risk in women after metabolic complications in pregnancy

Hypertensive pregnancy disorders complicate 10% of all pregnancies. In this article we discuss the spectrum of hypertensive conditions that may occur during pregnancy. Recent studies have consistently shown that hypertensive disorders in pregnancy implicate a two-fold higher risk for the development of hypertension and cardiovascular disease later in life. To optimise preventive management of cardiovascular disease in women with previous complicated pregnancies, we therefore recommend monitoring of hypertension and other cardiac risk factors at an early stage in life. Furthermore, the obstetric history should be routinely incorporated in cardiovascular risk assessment in women who seek medical attention for hypertension and/or cardiac symptoms. (Neth Heart J 2007;15:415-7.)     

Hypoxia Induces Transforming Growth Factor-β1 Gene Expression in the Pulmonary Artery of Rats via Hypoxia-inducible Factor-1α

The present study was undertaken to investigate the dynamic expression of hypoxia induciblefactor-1 α (HIF-1α) and transforming growth factor-β1 (TGF-β1) in hypoxia-induced pulmonary hypertensionof rats.It was found that mean pulmonary arterial pressure (mPAP) increased significantly after 7 d ofhypoxia.Pulmonary artery remodeling index and right ventricular hypertrophy became evident after 14 d ofhypoxia.HIF-1α mRNA staining was less positive in the control,hypoxia for 3 d and hypoxia for 7 d,butbegan to enhance significantly after 14 d of hypoxia,then remained stable.Expression of HIF-1 α protein inthe control was less positive,but was up-regulated in pulmonary arterial tunica intima of all hypoxic rats.TGF-β1 mRNA expression in pulmonary arterial walls was increased significantly after 14 d of hypoxia, butshowed no obvious changes after 3 or 7 d of hypoxia.In pulmonary tunica adventitia and tunica media,TGF-β1 protein staining was less positive in control rats,but was markedly enhanced after 3 d of hypoxia,reaching its peak after 7 d of hypoxia,and then weakening after 14 and 21 d of hypoxia.Western blottingshowed that HIF- 1α protein levels increased significantly after 7 d of hypoxia and then remained at a highlevel. TGF-β1 protein level was markedly enhanced after 3 d of hypoxia,reaching its peak after 7 d ofhypoxia,and then decreasing after 14 and 21 d of hypoxia.Linear correlation analysis showed that HIF-1αmRNA, TGF-β1 mRNA, TGF-β1 protein were positively correlated with mPAP,vessel morphometry andright ventricular hypertrophy index.TGF-β1 protein (tunica adventitia) was negatively correlated withHIF-lα mRNA.Taken together,our results suggest that changes in HIF-lα and TGF-β1 expression afterhypoxia play an important role in hypoxia-induced pulmonary hypertension of rats.     

c-Src kinase contributes on endothelial cells mechanotransduction in a heat shock protein 70-dependent turnover manner

Shear stress changes are associated with a repertory of signaling cascade modulating vascular phenotype. As shear stress-related tensional forces might be associated with pathophysiological susceptibility, a more comprehensive molecular map needs to be addressed. Thus, we subjected human umbilical vein endothelial cells (HUVECs) to a circuit of different tensional forces in vitro considering the following three groups: (a) physiological blood flow shear stress condition (named Normo), (b) a hypertensive blood flow shear stress (named Hyper), and (c) these hyper-stressed cells were returned to Normo condition (named Return). The samples were properly collected to allow different methodologies analysis. Our data showed a pivotal involvement of c-Src on driving the mechanotransduction cascade by modulating signaling related with adhesion, survival (PI3K/Akt) and proliferative phenotype. Moreover, c-Src seems to develop important role during extracellular matrix remodeling. Additionally, proteomic analysis showed strong involvement of heat shock protein 70 (HSP70) in the hypertensive-stressed cells; it being significantly decreased in return phenotype. This result prompted us to investigate 20S proteasome as an intracellular proteolytic alternative route to promote the turnover of those proteins. Surprisingly, our data reveled significant overexpression of sets of proteasome subunit α-type (PSMA) and β-type (PSMB) genes. In conjunction, our data showed c-Src as a pivotal protein to drive mechanotransduction in endothelial cells in a HSP70-dependent turnover scenario. Because shear patterns is associated with pathophysiological changes, such as atherosclerosis and hypertension, these results paved new road to understand the molecular mechanism on driving mechanotransduction in endothelial cells and, if drugable, these targets must be considered within pharmacological treatment optimization.     

苹果多酚对野百合碱诱导的肺动脉高压大鼠肺血管重构的作用和机制

目的:探讨苹果多酚抑制肺动脉高压大鼠肺动脉血管重构的作用及其机制。方法:雄性SD大鼠随机分为对照组(Con),野百合碱(MCT)组,苹果多酚(APP)组,野百合碱+苹果多酚(MCT+APP)组,每组9只。Con组:每天皮下注射1ml生理盐水;APP组:隔天按20mg/kg的剂量腹腔注射苹果多酚;MCT组:按60mg/kg剂量一次性皮下注射MCT;MCT+APP组:一次性皮下注射60mg/kg剂量MCT,隔天按20mg/kg剂量腹腔注射APP,所有处理持续3周。建模完成后,检测各组大鼠平均肺动脉压(mPAP),肺血管阻力(PVR),右心室肥厚指数(RVHI),肺动脉血管环外周长比值(WT%),肺小血管管壁面积和管总面积比值(WA%)。检测肺组织中的白细胞介素1(IL-1),白细胞介素6(IL-6),肿瘤坏死因子α(TNF-α),环氧化酶2(COX-2),髓过氧化物酶(MPO)等炎症通路相关指标,及肺动脉平滑肌细胞内Ca2+和内皮细胞eNOS,NO含量。结果:MCT组大鼠与对照组比较,在动物水平的指标mPAP、PVR、RVHI、WA%、WT%和肺动脉组织内IL-1,IL-6,TNF-α,COX-2,MPO表达量以及肺动脉平滑肌细胞内的Ca2+浓度明显升高(P<0.05),而内皮细胞中的eNOS,NO含量明显下降(P<0.05);苹果多酚治疗组与MCT组大鼠相比上述情况得到改善,其中COX-2和Ca2+指标明显下降,且具有统计学意义(P<0.05)。结论:苹果多酚可通过抑制MCT引起的肺组织内IL-1,IL-6,TNF-α,COX-2升高和肺动脉平滑肌细胞内Ca2+升高以及内皮细胞中eNOS,NO降低,抑制平滑肌细胞增殖,逆转肺血管重构,缓解肺动脉高压。     

甘西鼠尾草对大鼠高原肺动脉高压的干预作用及机制*

目的:探讨甘西鼠尾草(SPM)对大鼠高原肺动脉高压(HAPH)的干预作用及可能的机制。方法:将雄性SD大鼠随机分成对照组、缺氧组、SPM(0.5 g/kg、1 g/kg、2 g/kg)剂量组,每组14只,对照组饲养于西宁(海拔约2260 m),其余组均饲养于玛多县人民医院(海拔约4260 m)。SPM剂量组灌胃不同浓度的SPM(1 ml/100 g),浓度分别为0.5 g/kg、1 g/kg、2 g/kg,对照组和缺氧组灌胃等体积蒸馏水,每日一次,连续4周后,测定大鼠平均肺动脉压(mPAP)并取相同部位肺组织置液氮保存备用。采用RT-PCR法测定每组大鼠肺组织中的细胞增殖核抗原(PCNA)、细胞周期素依赖激酶(CDK4)、细胞周期蛋白D(CyclinD1)、RhoA(Ras同源基因家族成员A)、ROCK1、ROCK2的mRNA表达水平。结果:与对照组比较,缺氧组大鼠mPAP、肺组织中PCNA、CDK4、CyclinD1、RhoA、ROCK1、ROCK2的mRNA表达水平均明显升高(P＜0.01)。与缺氧组比较,SPM剂量组大鼠的mPAP、肺组织中PCNA、CDK4、CyclinD1、RhoA、ROCK1、ROCK2的mRNA表达水平均明显降低(P＜0.05或P＜0.01)。结论:SPM对大鼠HAPH具有一定的预防作用,其机制可能与抑制肺动脉平滑肌细胞过度增殖和RhoA/Rho激酶(ROCK)信号通路过度激活有关。     

Extracellular cAMP inhibits D1 dopamine receptor expression in CAD catecholaminergic cells via A2a adenosine receptors

The expression of D1 dopamine (DA) receptor gene is regulated during development, aging, and pathophysiology. The extracellular factors and signaling mechanisms that modulate the expression of D1 DA receptor have not been well characterized. Here, we present novel evidence that endogenous D1 DA receptor expression is inhibited by extracellular cAMP in the Cath.A Derived (CAD) catecholaminergic neuronal cell line. CAD cells express the multi-drug resistance protein 5 transporters and secrete cAMP. Addition of exogenous cAMP decreases D1 receptor mRNA and protein greater than fourfold in 24 h. The cAMP-induced decrease of D1 receptor mRNA levels is blocked by cGMP and by 1,3-dipropyl-8-(p-sulfo-phenyl)xanthine, an inhibitor of ecto-phosphodiestrase. Extracellular AMP, a metabolite of cAMP, also independently decreased D1 receptor mRNA levels. Inhibitors of ecto-nucleotidases, alpha,beta-methyleneadenosine 5'-di-phosphate and GMP, completely blocked the decrease of D1 receptor mRNA by extracellular cAMP, but only partially blocked the decrease induced by extracellular AMP. Levamisole, an inhibitor of tissue non-specific alkaline phosphatase, completely blocked the AMP-induced decrease of D1 receptor mRNA. The extracellular cAMP, AMP, and adenosine (ADO)-induced decrease in D1 receptor mRNA expression are mediated by A2a ADO receptor subtype. The results suggest a novel molecular mechanism linking activation of A2a ADO receptors with inhibition of D1 DA receptor expression.