高血压合并OSAHS患者经鼻持续气道正压通气治疗前后血压与血清脂联素水平变化的研究

目的观察分析经鼻持续气道正压通气（ncPAP）治疗对高血压合并中重度（）sAHS患者血压及血清脂联素水平的影响。方法人选研究对象60例,诊断高血压合并中重度0SAHS明确,随机分为nCPAP治疗组与对照组。治疗组患者在治疗前后分别比较两组不同时间点血压及血清脂联素水平的变化,分析治疗对高血压合并中重度OSAHS患者血压及脂联素的影响。结果治疗后患者血压、血清脂联素水平均有所下降,晨起血压及脂联素下降较为显著。晨起血压差值与血清脂联素差值呈正相关。结论ncPAP治疗可有效降低高血压合并中重度0sAHs患者血压及血清脂联素水平,且晨起血压的变化与脂联素的变化呈正相关。     

脂联素在肥胖相关疾病中的作用

脂联素(APN)是白色脂肪等组织分泌的一种循环激素,在调节糖、脂代谢和抗炎中起重要作用。肥胖患者的血浆脂联素水平明显降低,低脂联素血症已被确认是2型糖尿病、冠心病和高血压等肥胖相关疾病的独立危险因素。本文就脂联素的结构、功能及其在胰岛素抵抗等代谢性疾病、冠状动脉硬化和高血压性心脏病中的保护作用作一综述。     

脂联素的血管及心肌保护作用

脂联素是由脂肪细胞分泌的一种内源性生物活性多肽.多项研究结果表明,脂联素具有抗炎、抗动脉粥样硬化、抑制新生血管、抗氧化应激及调节能量代谢等心血管保护作用.流行病学调查亦显示:在一些肥胖相关疾病的患者体内,脂联素水平的降低与心血管疾病风险增加相关.脂联素的作用机制复杂,与多种信号转导通路有关.脂联素有望为糖尿病心血管疾病...     

冠心病患者血浆脂联素、血红素加氧酶1与冠状动脉病变程度的相关性

目的 通过测定冠心病患者血浆脂联素和血红素加氧酶1水平,分析其与冠状动脉病变程度之间的相关性,探讨两者在冠心痛中的相互作用.方法 ELISA法测定冠心病组、非冠心病对照组血浆脂联素、血红素加氧酶1的水平,分别比较二者之间的相关性及其与冠状动脉病变程度(Gensini积分)的相关性.结果 冠心痛组血浆脂联素、血红素加氧酶1水平均较对照组显著降低(4.87±0.24比13.51±0.93mg/L,P<0.001:38.85±2.86比220.00±28.11μg/L,P<0.001).按冠状动脉病变支数进一步分组,冠状动脉病变支数多者血浆脂联素、血红素加氧酶1水平较冠状动脉病变支数少者亦显著降低.脂联素与血红素加氧酶1呈正相关(r=0.551,P<0.001),Gensini积分分别与血浆脂联素、血红素加氧酶1水平呈负相关(r=-0.526,P<0.001;r=-0.451,P<0.001).结论 冠心病患者血浆脂联素与血红素加氧酶1密切相关,且与冠状动脉病变程度密切相关,两者之间可能存在相互调节的作用.     

脂联素与心血管疾病的研究现状与展望

肥胖与心血管疾病及代谢紊乱密切相关。脂联素是一种脂肪源性血浆蛋白,在与肥胖相关的代谢紊乱及疾病中含量降低,低脂联素水平与肥胖相关的心血管疾病危险性增加有关。有研究表明,脂联素可直接作用于心肌及血管细胞发挥作用,可通过多种机制保护心血管系统。其中主要包括调节一磷酸腺苷活性蛋白酶介导的信号通路、抑制炎症与促进内皮细胞功能等。脂联素所共有的调节代谢、抗炎及血管保护、心肌保护作用,可为临床治疗代谢综合征性心血管疾病,提供新的干预靶点和治疗思路。     

脂联素研究进展及其与康复运动的关系

脂联素（adiponectin）是脂肪细胞分泌的一种激素蛋白，具有调节能量平衡、增强胰岛素敏感性、抗炎、抗动脉粥样硬化等广泛的生物学作用。脂联素在健康机体血浆中含量丰富，但在肥胖、2型糖尿病、冠心病及原发性高血压等状态下，脂联素水平降低。康复作为一种对机体的有益刺激能否影响患者体内脂联素水平，是近年来研究的热点，本文对此做一综述。     

低脂联素血症可预测罹发高血压风险

据悉，循环血中的脂联素，系一种脂肪衍生的兼有胰岛素增敏性、抗炎和抗动脉粥样硬化特性的激素。晚近发现，无论在高血压病人或在高血压动物中，均存在低循环水平的脂联素；相反，补充脂联素皆能改善伴低脂联素血症的无论高血压病人或动物的高血压状态，既而提示脂联素降低可能为高血压的病因之一。现就低脂联素血症可否预测人类高血压风险进行长程调查分析。     

血红素氧化酶的心血管系统作用研究

血红素氧化酶的功能是进行血红素代谢，生成一氧化碳、胆红素和铁。一氧化碳增加细胞内环磷鸟,调节血管平滑肌张力，产生扩张血管的效应；同时生成的血红素则有抗氧化的作用。本文就血红素氧化酶在心血管系统中的作用机制作一综述。     

血红素氧化酶的心血管系统作用研究

血红素氧化酶的功能是进行血红素代谢,生成一氧化碳、胆红素和铁.一氧化碳增加细胞内环磷鸟苷,调节血管平滑肌张力,产生扩张血管的效应;同时生成的血红素则有抗氧化的作用.本文就血红素氧化酶在心血管系统中的作用机制作一综述.     

脂联素在冠状动脉粥样硬化性心脏病中的重要作用

脂联素是由脂肪细胞等分泌的一种具有心血管保护作用的细胞因子。脂联素可以通过多种信号通路发挥抗炎、抗动脉硬化、抗栓、抗纤维化、保护血管内皮及调节糖脂代谢的作用。     

Carbon monoxide and hypertension

The enzymatic action of heme oxygenase yields carbon monoxide, biliverdin and iron. Carbon monoxide is implicated in many physiological processes, including the regulation of vascular tissue contractility and apoptosis. By stimulating the soluble guanylyl cyclase (sGC)/cGMP pathway and activating K channels in vascular smooth muscle cells (SMCs), carbon monoxide relaxes vascular tissues under physiological conditions. Altered metabolism and functions of carbon monoxide have been linked to the pathogenesis and maintenance of hypertension. The expression and activity of heme oxygenase-1, sGC and cGMP in vascular SMCs are associated with different stages of development of hypertension in spontaneously hypertensive rats (SHRs). The importance of altered heme oxygenase-2 expression in vascular tissues in hypertension remains unclear. Increased vascular contractility, unbalanced cellular apoptosis and proliferation in the vascular wall, increased oxidative stress, and the altered interaction of carbon monoxide and nitric oxide are among the consequences of heme oxygenase/carbon monoxide system dysfunction in hypertension. Acute application of pharmacological inducers to upregulate the expression of heme oxygenase-1 or the use of gene delivery method to overexpress heme oxygenase-1 decreases blood pressure in young SHRs and other animal models of hypertension. These blood pressure-decreasing effects are annulled by metalloporphyrins. In adult SHRs, the heme oxygenase/carbon monoxide system appears to be normalized as a compensatory reaction. To date, acute manipulation of the expression of heme oxygenase-1 has not been successful in decreasing blood pressure in adult SHRs. In conclusion, abnormality of the heme oxygenase/carbon monoxide system has a critical role in the pathogenesis of hypertension, and novel therapeutic approaches should be pursued to achieve selective improvement in the function of this system in hypertension.     

Interaction of carbon monoxide and adenosine in the nucleus tractus solitarii of rats

Carbon monoxide has been identified as an endogenous biological messenger in the brain. Heme oxygenase catalyzes the metabolism of heme to carbon monoxide and biliverdin. Previously, we have shown the involvement of carbon monoxide in central cardiovascular regulation, baroreflex modulation, and glutamatergic neurotransmission in the nucleus tractus solitarii of rats. We also showed that adenosine increased the release of glutamate in the nucleus tractus solitarii. In this study, we investigated the possible interactions of carbon monoxide and adenosine in the nucleus tractus solitarii. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure were monitored intra-arterially. Unilateral microinjection of increasing doses of hemin (0.01 to 3.3 nmol), a heme molecule cleaved by heme oxygenase to yield carbon monoxide, produced a significant decrease in blood pressure and heart rate in a dose-dependent manner. In addition, similar cardiovascular effects were observed after injection of adenosine (2.3 nmol). These cardiovascular effects of hemin were attenuated by prior administration of the adenosine receptor antagonist 1,3-dipropyl-8-sulfophenylxanthine. Similarly, pretreatment of the heme oxygenase inhibitor zinc protoporphyrin IX or zinc deuteroporphyrin 2,4-bis glycol also attenuated the depressor and bradycardic effects of adenosine. These results indicate that the interaction between carbon monoxide and adenosine may contribute to the activation of heme oxygenase in central cardiovascular regulation.     

Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats

BACKGROUND/AIMS: The pathophysiological significance of heme oxygenase-1 up-regulation in portal hypertension is not completely understood. In this study, we determined the role of heme oxygenase-1 on oxidative stress, inflammation, angiogenesis, and splanchnic hemodynamics in rats with portal hypertension induced by partial portal vein ligation. METHODS: Rats were treated with the heme oxygenase inhibitor SnMP or vehicle for 7 days. Then, oxidative stress was quantified by superoxide anion production, and inflammatory response was assessed by immunofluorescence. Expression of angiogenesis mediators was determined by western blotting, and the extent of portosystemic collaterals by radioactive microspheres. Hemodynamic studies were performed by flowmetry. RESULTS: Oxidative stress was significantly increased in the mesentery of portal hypertensive rats, as compared with sham-operated controls. In portal hypertensive rats, chronic heme oxygenase inhibition (1) potentiated oxidative stress and inflammation, (2) significantly decreased VEGF expression, without modifying the extent of collaterals or the splanchnic neovascularization, and (3) significantly decreased superior mesenteric artery blood flow and portal pressure. CONCLUSIONS: This study demonstrates that heme oxygenase plays an important (beneficial) role attenuating oxidative stress and inflammation, but it also plays a detrimental role in stimulating VEGF production, and contributing to the development of hyperdynamic splanchnic circulation in rats with portal hypertension.     

Modulatory effects of carbon monoxide on baroreflex activation in nucleus tractus solitarii of rats

Recent studies suggest that carbon monoxide (CO), which is produced in significant quantities in many brain regions, may function as a neurotransmitter. Heme oxygenase catalyzes the metabolism of heme to CO and biliverdin; however, the physiological role of CO in central cardiovascular regulation was not well understood. In the present study, we evaluated the baroreflex response of CO in the nucleus tractus solitarii (NTS) of rats. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure and heart rate were monitored intra-arterially. Unilateral microinjection (60 nL) of hematin, a heme molecule cleaved by heme oxygenase to yield CO, into the NTS produced prominent dose-related depressor and bradycardic effects. Baroreflex responses were elicited by increasing doses of phenylephrine (10 to 30 microg/kg IV) before and after intra-NTS administration of zinc deuteroporphyrin 2,4-bis-glycol (ZnDPBG) (1 nmol), an inhibitor of heme oxygenase activity, or vehicle alone. The reflex bradycardia elicited by phenylephrine was significantly inhibited by pretreatment with ZnDPBG. Furthermore, the inhibitory effect of ZnDPBG on baroreflex activation was dose dependent. These results suggest CO formed by brain heme oxygenase plays a significant role in central cardiovascular regulation and that inhibition of heme oxygenase attenuated baroreflex activation.     

Increased heme oxygenase activity in splanchnic organs from portal hypertensive rats: role in modulating mesenteric vascular reactivity

BACKGROUND/AIMS: We have recently demonstrated that heme oxygenase-1 is upregulated in splanchnic organs of portal hypertensive rats. In the present study, we assessed whether heme oxygenase enzymatic activity is increased in splanchnic organs of portal hypertensive rats, and the relative contribution of heme oxygenase and nitric oxide synthase to the vascular hyporeactivity in portal hypertension. METHODS: Heme oxygenase activity was measured in splanchnic organs of portal hypertensive and sham-operated rats. The effects of heme oxygenase and nitric oxide synthase inhibition on pressure responses to potassium chloride and methoxamine were assessed in perfused mesenteric vascular beds of portal hypertensive and sham-operated rats. RESULTS: Heme oxygenase activity was increased in the mesentery, intestine, liver, and spleen of portal hypertensive rats. The hyporeactivity to potassium chloride in portal hypertensive rats was overcome after simultaneous inhibition of both heme oxygenase and nitric oxide synthase, but only partially attenuated after nitric oxide synthase inhibition alone. The hyporeactivity to methoxamine was completely reversed after nitric oxide synthase blockade. CONCLUSIONS: These results demonstrate that heme oxygenase activity is increased in splanchnic organs of portal hypertensive rats. They also suggest that heme oxygenase contributes to the hyporeactivity to potassium chloride, but not to methoxamine, in portal hypertensive rats.     

Crosstalk between the heme oxygenase system, aldosterone, and phospholipase C in hypertension

BACKGROUND: Aldosterone is a mineral corticoid hormone that is produced in response to angiotensin-II, and like angiotensin-II, stimulates inflammation, oxidative stress, and fibrosis by activating nuclear factor-kappaB and activating protein-1. Recent evidence, however, indicates that aldosterone stimulates phospholipase C and activates nuclear factor-kappaB and activating protein-1. Although the heme oxygenase system is cytoprotective, its effects on aldosterone-phospholipase C signaling in deoxycorticosterone acetate (DOCA-salt) hypertension, a model of aldosteronism, and spontaneously hypertensive rat, a genetic model of human essential hypertension, have not been fully characterized. METHODS: In the present study, the heme oxygenase inducer, hemin, was given to spontaneously hypertensive and deoxycorticosterone acetate hypertensive rats, and the effects on blood pressure, aldosterone, nuclear factor-kappaB, activating protein-1, phospholipase C, and inositol 1,4,5-triphosphate were examined. RESULTS: Hemin therapy restored physiological blood pressure to spontaneously hypertensive rats (209.9 +/- 0.9 to 127.3 +/- 0.85 mmHg, n = 10, P < 0.01) and to deoxycorticosterone acetate salt hypertensive rats (195.7 +/- 1.8 vs.132.5 +/- 2.1 mmHg; P < 0.01, n = 10), but had no effect on age-matched normotensive Wistar-Kyoto or Sprague-Dawley strains. The antihypertensive effect was accompanied by enhanced heme oxygenase activity, upregulated cyclic guanosine monophosphate-protein kinase G signaling, increased superoxide dismutase activity, and the potentiation of total antioxidant capacity, whereas aldosterone, activating protein-1, and nuclear factor-kappaB were reduced. Furthermore, hemin suppressed phospholipase C activity, attenuated inositol 1,4,5-triphosphate, and reduced resting intracellular calcium in the aorta. CONCLUSION: Collectively, our results suggest that the concomitant depletion of aldosterone, phospholipase C-inositol 1,4,5-triphosphate activity, resting intracellular calcium and the corresponding decline of inflammatory, and oxidative insults may account for the antihypertensive effects of hemin in deoxycorticosterone acetate hypertension and spontaneously hypertensive rats.     

血红素加氧酶/一氧化碳在血管平滑肌细胞中的研究

血红素加氧酶是哺乳动物中血红素代谢的限速酶,它能分解血红素成胆绿素、一氧化碳和铁.其中血红素加氧酶-1又称诱导型血红素加氧酶,它在血管平滑肌细胞中表达,可以被诸多因素所诱导.由血红素加氧酶-1催化产生的一氧化碳是一种重要的内源性生物信使,目前研究已经表明了它在循环系统中的重要作用.血管平滑肌细胞的增殖和凋亡是众多的心血管疾病如高血压、动脉粥样硬化的病理基础.血红素加氧酶/一氧化碳系统与血管平滑肌细胞的增殖和凋亡有着密切的关系.目前研究发现不少心血管药物通过该系统影响平滑肌细胞的增殖和凋亡,为新药物的开发奠定了基础.     

Identification of heme oxygenase and cytochrome P-450 in the rabbit heart

The regulation of cardiac heme oxygenase and cytochrome P-450 mixed function oxidase was studied in the rabbit heart. Heme oxygenase activity is found in ventricular and atrial microsomal fractions. This activity is NADPH dependent, and is inhibited by tin and zinc protoporphyrin, but not by either SKF 525A or 7,8-benzoflavone. Immunologic studies of cardiac heme oxygenase demonstrate that antibodies prepared against human purified hepatic heme oxygenase recognize rabbit atrial heme oxygenase and inhibit the enzyme activity by 92%. In contrast, control immunoglobulin does not inhibit heme oxygenase activity. Further, the western blotting technique demonstrates that a similar band of protein with a molecular weight of 32,000 exists in cardiac microsomes and that no protein cross-reacts with purified hepatocyte heme oxygenase. Marked induction of atrial heme oxygenase is observed in microsomal fractions prepared from rabbits treated with cobalt chloride. Atrial microsomes possess 0.24 nmol of cytochrome P-450 as compared to 0.68 nmol/mg protein in microsomes from the liver. The levels of aryl hydrocarbon hydroxylase (AHH) activity, a cytochrome P-450-dependent enzyme, in ventricle and atrium are stimulated by a NADPH-generating system and are sensitive to 7,8-benzoflavone, and SKF 525A, known inhibitors of cytochrome P-450 mixed function oxidase. AHH activity in ventricular and atrial microsomes is 2-3% of that seen in liver microsomes whereas the P-450 content/mg protein is about 20% of that observed in the liver. AHH activity is mediated by a form of cytochrome P-450 that is inducible by 3-methylcholanthrene/beta-naphthoflavone. A possible new role of the heart cytochrome P-450 system in cardiac function is proposed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human heme oxygenase-1 gene transfer lowers blood pressure and promotes growth in spontaneously hypertensive rats

Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, with release of free iron and carbon monoxide. Both heme and carbon monoxide have been implicated in the regulation of vascular tone. A retroviral vector containing human HO-1 cDNA (LSN-HHO-1) was constructed and subjected to purification and concentration of the viral particles to achieve 5x10(9) to 1x10(10) colony-forming units per milliliter. The ability of concentrated infectious viral particles to express human HO-1 (HHO-1) in vivo was tested. A single intracardiac injection of the concentrated infectious viral particles (expressing HHO-1) to 5-day-old spontaneously hypertensive rats resulted in functional expression of the HHO-1 gene and attenuation of the development of hypertension. Rats expressing HHO-1 showed a significant decrease in urinary excretion of a vasoconstrictor arachidonic acid metabolite and a reduction in myogenic responses to increased intraluminal pressure in isolated arterioles. Unexpectedly, HHO-1 chimeric rats showed a simultaneous significant proportionate increase in somatic growth. Thus, delivery of HHO-1 gene by retroviral vector attenuates the development of hypertension and promotes body growth in spontaneously hypertensive rats.