Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). Heme-derived CO inhibits nitric oxide synthase and promotes endothelium-dependent vasoconstriction. After 4 wk of high-salt diet, Dahl salt-sensitive (Dahl-S) rats display hypertension, increased vascular HO-1 expression, and attenuated vasodilator responses to ACh that can be completely restored by acute treatment with an inhibitor of HO. In this study, we examined the temporal development of HO-mediated endothelial dysfunction in isolated pressurized first-order gracilis muscle arterioles, identified the HO product responsible, and studied the blood pressure effects of HO inhibition in Dahl-S rats on a high-salt diet. Male Dahl-S rats (5-6 wk) were placed on high-salt (8% NaCl) or low-salt (0.3% NaCl) diets for 0-4 wk. Blood pressure increased gradually, and responses to an endothelium-dependent vasodilator, ACh, decreased gradually with the length of high-salt diet. Flow-induced dilation was abolished in hypertensive Dahl-S rats. Acute in vitro pretreatment with an inhibitor of HO, chromium mesoporphyrin (CrMP), restored endothelium-dependent vasodilation and abolished the differences between groups. The HO product CO prevented the restoration of endothelium-dependent dilation by CrMP. Furthermore, administration of an HO inhibitor lowered blood pressure in Dahl-S rats with salt-induced hypertension but did not do so in low-salt control rats. These results suggest that hypertension and HO-mediated endothelial dysfunction develop gradually and simultaneously in Dahl-S rats on high-salt diets. They also suggest that HO-derived CO underlies the impaired endothelial dysfunction and contributes to hypertension in Dahl-S rats on high-salt diets.
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PMID:Heme oxygenase-derived carbon monoxide promotes arteriolar endothelial dysfunction and contributes to salt-induced hypertension in Dahl salt-sensitive rats. 1552 97

The enzyme heme oxygenase (HO) has been implicated in several physiological functions throughout the body including control of vascular tone and regulation of the inflammatory and apoptotic cascades as well as contributing to the antioxidant capabilities in several organ systems. These various properties attributed to HO are carried out through the catalytic products of heme degradation, namely carbon monoxide (CO), biliverdin, and free iron (Fe2+). As the newly emerging roles of HO in normal organ function have come to light, researchers in several disciplines have assessed the role of this enzyme in various physiological and pathological changes taking place in the human body over a lifetime. Included in this new wave of interest is the involvement of HO, and its by-products, in the normal function of the vital organ of pregnancy, the placenta. In this review the role of HO, and its catalytic products, will be examined in the context of pregnancy. The different isoforms of the HO enzyme (HO-1, HO-2, HO-3) have been localized throughout placental tissue, and have been shown to be physiologically active. The HO protein and more specifically its catalytic by-products (CO, biliverdin, and Fe2+) have been postulated to be involved in the maintenance of uterine quiescence throughout gestation, regulation of hemodynamic control within the uterus and placenta, regulation of the apoptotic and inflammatory cascades in trophoblast cells, and the maintenance of a balance of the oxidant-antioxidant status within the placental tissues. The association between this enzyme system, and its above-noted roles throughout pregnancy, with the hypertensive disorder of pregnancy preeclampsia (PET), will also be examined. It is hypothesized that a decrease in HO expression and/or activity throughout gestation would be capable of initiating several pathological processes involved in the etiology of PET. This hypothesis has led to further discussion emphasizing the possibility of novel therapeutic designs targeting this enzyme system for the treatment of PET.
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PMID:HO in pregnancy. 1578 Jul 56

Overproduction of reactive oxygen species under pathophysiological conditions, including dyslipidemia, hypertension, diabetes, and smoking, is integral in the development of cardiovascular diseases (CVD). The reactive oxygen species released from all types of vascular cells regulate various signaling pathways that mediate not only vascular inflammation in atherogenesis but also antioxidative and antiinflammatory responses. One such protective and stress-induced protein is heme oxygenase (HO). HO is the first rate-limiting enzyme in heme breakdown to generate equimolar quantities of carbon monoxide, biliverdin, and free ferrous iron. Accumulating evidence has shown that inducible HO (HO-1) and its products function as adaptive molecules against oxidative insults. The proposed mechanisms by which HO-1 exerts its cytoprotective effects include its abilities to degrade the pro-oxidative heme, to release biliverdin and subsequently convert it bilirubin, both of which have antioxidant properties, and to generate carbon monoxide, which has antiproliferative and antiinflammatory as well as vasodilatory properties. Herein, I highlight the relationship of HO and cardiovascular disease, especially atherosclerosis, gene-targeting approaches in animal models, and the potential for and concern about HO-1 as a novel therapeutic target for cardiovascular diseases.
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PMID:Heme oxygenase and atherosclerosis. 1602 Jul 46

The discovery of nitric oxide (NO) initiated a novel research field, gaseous signal molecules. Other two gaseous signal molecules, carbon monoxide (CO) and hydrogen sulfide (H2S), have been approved subsequently. All of these three gaseous signal molecules are generated endogenously and exert extensive biological effects. This article reviews the significance of gaseous signal molecules in the pathogenesis of cardiovascular diseases. In the cardiovascular system, the endogenous NO, CO and H2S form three specific and relevant pathways with their corresponding enzymes including nitric oxide synthase (NOS), heme oxygenase (HO), and cystathionine-gamma-lyase (CSE). The gaseous signal molecules not only participate in the maintenance of physiological function and structure of the cardiovascular system, but also exert important pathophysiological effects in the pathogenesis of cardiovascular diseases, such as hypertension, pulmonary hypertension, septic shock and atherosclerosis. Further studies on gaseous signal molecules will remarkably promote the basic research in the cardiovascular fields, and provide a novel direction for the clinical research as well.
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PMID:[Significance of gaseous signal molecule in the pathogenesis of cardiovascular diseases]. 1617 52

Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme-derived CO inhibits nitric oxide synthase and can contribute to hypertension via endothelial dysfunction in Dahl salt-sensitive rats. Obese Zucker rats (ZR) are models of metabolic syndrome. This study tests the hypothesis that endogenous CO formation is increased and contributes to hypertension and endothelial dysfunction in obese ZR. Awake obese ZR showed increased respiratory CO excretion, which was lowered by HO inhibitor administration [zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG) 25 micromol.kg(-1).24 h(-1) ip]. In awake obese ZR, chronically instrumented with femoral arterial catheters, blood pressure was elevated but was decreased by the HO inhibitor ZnDPBG. Body weight, blood glucose, glycated hemoglobin, plasma insulin, total and LDL cholesterol, oxidized LDL, and triglyceride levels were elevated in obese ZR, and, except for LDL cholesterol, were unchanged by HO inhibition. Total HO-1 protein levels were not different between lean and obese ZR aortas. In vitro experiments used isolated skeletal muscle arterioles with constant pressure and no flow, or constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow. In obese ZR arterioles, responses to ACh and flow were attenuated. Acute in vitro pretreatment with an HO inhibitor, chromium mesoporphyrin, enhanced ACh and flow-induced dilation and abolished the differences between groups. Furthermore, exogenous CO prevented the restoration of flow-induced dilation by the HO inhibitor in obese ZR arterioles. These results suggest that HO-derived CO production is increased and promotes hypertension and arteriolar endothelial dysfunction in obese ZR with metabolic syndrome independent of affecting metabolic parameters.
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PMID:Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats. 1628 90

Hemin and other heme derivatives, e.g. heme-L-lysinate (HLL) and heme-L-arginate, have been used extensively to upregulate expression of heme oxygenase and production of endogenous carbon monoxide. Hemin administration has been shown to markedly decrease high blood pressure in spontaneously hypertensive rats (SHR), but not in normotensive Wistar-Kyoto or Sprague Dawley (SD) rats. While methodology to measure serum heme levels has been established long ago, metabolism of the injected hemin or heme derivatives when used to lower blood pressure has not been investigated. In this study, metabolism of hemin or HLL after injected into the rat was monitored by measuring changes in circulatory heme levels. SHR (12-20 weeks old) had significantly higher blood pressure than age-matched SD rats. In both strains, serum heme level was negligible. Hemin or HLL injection (15 mg/kg/day, i.p.) for 5-13 days significantly lowered blood pressure of 12-weeks SHR. High blood pressure was not lowered in SHR older than 20 weeks until hemin or HLL injection period was beyond 5 days. This anti-hypertensive effect of hemin and HLL was synchronized with an increase in serum heme level, from undetectable to 4.3 micromol/l. On the other hand, hemin or HLL had no effect on blood pressure of age-matched SD rats, despite serum heme level rose to the same extent as in the treated SHR. There was no significant difference between hemin and HLL injections in terms of changes in blood pressure and serum heme level in all rats. Our study for the first time correlated changes in serum heme levels with blood pressure levels after injection of hemin or HLL in SHR and SD rats. Hemin and HLL had similar effects on blood pressure change and serum heme level. By determining serum heme levels following the administration of hemin or HLL, we can better understand mechanisms for the blood pressure lowering effect of hemin therapy. Application of this heme monitoring technology will also pave the way for clinical application of hemin therapy in treatment of different types of hypertension pathologies.
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PMID:Monitoring circulatory heme level in hemin therapy for lowering blood pressure in rats. 1630 73

To explore the underlying mechanism(s) of pulmonary arterial hypertension in endotoxic shock, the roles of N-acetylcysteine (NAC), nitric oxide (NO) and carbon monoxide (CO) were investigated. Pulmonary arterial rings (3-mm width) were prepared from 24 rabbits. Lipopolysaccharide (LPS), after 7-hour incubation, decreased the endothelium-dependent relaxation response of the arterial ring (pre-contracted with phenylephrine) to acetylcholine (1 mumol/L), but did not affect the endothelium-independent relaxation response to sodium nitroprusside. The LPS effects were reduced by a concomitant incubation with the free radical scavenger (NAC), NO donor (L-arginine), and CO donor (hemin), respectively. On the other hand, the LPS effects were enhanced by applying heme oxygenase-1 (HO-1) inhibitor (zinc protoporphyrin) to block CO production. The response to acetylcholine changed from relaxation to contraction, however, the contractile response to phenylephrine increased significantly after pre-incubation with nitric oxide synthase (NOS) inhibitor (L-NAME) to block NO production, confirming the importance of CO and NO. These results show that LPS impairs endothelium-dependent relaxation of the pulmonary artery, which can be greatly reduced by the antioxidant, or by supplying with NO and CO. Thus, multiple factors are involved in this model of endotoxin-induced pulmonary hypertension.
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PMID:Multiple factors contributing to lipopolysaccharide-induced reactivity changes in rabbit pulmonary artery. 1634 99

Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed by the enzyme heme oxygenase (HO). Inducible HO (HO-1) and constitutive HO (HO-2) are mostly recognized for their roles in the oxidation of heme and production of CO and biliverdin, whereas the biological function of the third HO isoform, HO-3, is still unclear. The tissue type-specific distribution of these HO isoforms is largely linked to the specific biological actions of CO on different systems. CO functions as a signaling molecule in the neuronal system, involving the regulation of neurotransmitters and neuropeptide release, learning and memory, and odor response adaptation and many other neuronal activities. The vasorelaxant property and cardiac protection effect of CO have been documented. A plethora of studies have also shown the importance of the roles of CO in the immune, respiratory, reproductive, gastrointestinal, kidney, and liver systems. Our understanding of the cellular and molecular mechanisms that regulate the production and mediate the physiological actions of CO has greatly advanced. Many diseases, including neurodegenerations, hypertension, heart failure, and inflammation, have been linked to the abnormality in CO metabolism and function. Enhancement of endogenous CO production and direct delivery of exogenous CO have found their applications in many health research fields and clinical settings. Future studies will further clarify the gasotransmitter role of CO, provide insight into the pathogenic mechanisms of many CO abnormality-related diseases, and pave the way for innovative preventive and therapeutic strategies based on the physiologic effects of CO.
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PMID:Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. 1638 9

Cadmium (Cd) is a metal toxin of continuing worldwide concern. Daily intake of Cd, albeit in small quantities, is associated with a number of adverse health effects which are attributable to distinct pathological changes in a variety of tissues and organs. In the present review, we focus on its renal tubular effects in people who have been exposed environmentally to Cd at levels below the provisional tolerable intake level set for the toxin. We highlight the data linking such low-level Cd intake with tubular injury, altered abundance of cytochromes P450 (CYPs) in the kidney and an expression of a hypertensive phenotype. We provide updated knowledge on renal and vascular effects of the eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and eicosatrienoic acids (EETs), which are biologically active metabolites from arachidonate metabolism mediated by certain CYPs in the kidney. We note the ability of Cd to elicit "oxidative stress" and to alter metal homeostasis notably of zinc which may lead to augmentation of the defense mechanisms involving induction of the antioxidant enzyme heme oxygenase-1 (HO-1) and the metal binding protein metallothionein (MT) in the kidney. We hypothesize that renal Cd accumulation triggers the host responses mediated by HO-1 and MT in an attempt to protect the kidney against injurious oxidative stress and to resist a rise in blood pressure levels. This hypothesis predicts that individuals with less active HO-1 (caused by the HO-1 genetic polymorphisms) are more likely to have renal injury and express a hypertensive phenotype following chronic ingestion of low-level Cd, compared with those having more active HO-1. Future analytical and molecular epidemiologic research should pave the way to the utility of induction of heme oxygenases together with dietary antioxidants in reducing the risk of kidney injury and hypertension in susceptible people.
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PMID:Kidney dysfunction and hypertension: role for cadmium, p450 and heme oxygenases? 1649 27

To investigate the anti-cardiac hypertrophic mechanism of statins, thirty-eight male Wistar rats were randomly allocated to four groups. Rats in model group received nitric oxide synthase inhibitor, N-nitro-L-arginine (L-NNA) 15 mg/(kg.d) by peritoneal injection. Rats in simvastatin treatment groups were given simultaneously L-NNA as those in model group and simvastatin 5 or 30 mg/(kg.d) intragastrically respectively. Rats in control group received the same volume of normal sodium. Left ventricular function, left ventricular mass index (LVMI), the content of brain natriuretic peptide (BNP) in plasma and myocardium, myocardial hydroxyproline and heme oxygenase activity were determined after 6 weeks. The results showed that rats in model group developed significant cardiac hypertrophy associated with reduced left ventricular function compared with the control group. However, compared with the model group, L-NNA-induced cardiac hypertrophy of rats was significantly relieved in simvastatin treatment groups, associated with improved left ventricular function, decreased LVMI, lower BNP levels in plasma and myocardium, lower content of myocardial hydroxyproline, and increased myocardial heme oxygenase (HO) activity. In cultured rat neonatal cardiomyocytes, simvastatin (30 or 100 mumol/L) significantly increased heme oxygenase-1 (HO-1) mRNA expression, HO activity as well as the production of CO in cardiomyocytes. Cultured with zinc protoporphyrin, a HO inhibitor, or simvastatin alone did not change [(3)H]leucine uptake of cardiomyocytes. However, cocultured with simvastatin significantly inhibited the cardiomyocyte [(3)H]leucine uptake induced by angiotensin II in a concentration-dependent manner. Cotreatment with zinc protoporphyrin significantly abolished the suppressive effect of simvastatin on cardiomyocyte [(3)H]leucine uptake. These data suggest that the activation of HO-1/CO pathway may be one of the important mechanisms by which statins inhibit cardiac hypertrophy caused by hypertension.
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PMID:[Simvastatin inhibits hypertension-induced cardiac hypertrophy in rats through activation of heme oxygenase-1/carbon monoxide pathway]. 1662 57


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