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)

Heme oxygenase enzymes (HO-1 and HO-2) catalyze the conversion of heme to biliverdin, free iron, and carbon monoxide (CO). Heme and products derived from its metabolism potentially influence renal function and blood pressure by affecting the expression and/or activity of hemeproteins, including cytochrome P450 (CYP4A) monooxygenases and cyclooxygenases (COX-1 and COX-2). We studied HO isoform expression and examined the effect of HO-1 induction by SnCl(2) on CYP4A and COX expression and activity in the rat kidney. HO-1 protein levels in kidney tissues from untreated rats were barely detectable, whereas HO-2 protein was expressed in all kidney structures examined and its levels were higher in the outer medulla followed by the inner medulla/papilla and cortex. HO-2 expression along the nephron followed its regional distribution, ie, the highest levels were detected in the medullary thick ascending limb (mTAL) and inner medullary collecting ducts followed by proximal tubules. SnCl(2) Treatment did not significantly affect HO-2 expression or distribution; however, it markedly increased HO-1 protein in the inner and outer medulla, specifically, in the inner medullary collecting ducts and mTAL. CYP4A expression and 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis were the highest in the outer medulla followed by the cortex and inner medulla/papilla. SnCl(2) treatment reduced cortical and inner medullary CYP4A protein levels by 60% and 50% and inhibited 20-HETE synthesis by 90% and 60%, respectively. Despite a significant induction of HO-1 protein in the outer medulla, CYP4A expression and 20-HETE synthesis were hardly affected. SnCl(2) treatment did not affect COX-1 expression but markedly reduced cortical and medullary COX-2 protein levels. We conclude that HO isoform expression is segmented within the kidney and along the nephron and that treatment with an HO-1 inducer suppressed the levels of CYP4A and COX-2 proteins in a tissue-specific manner with concomitant effects on their activity. Such interactions may play an important role in the regulation of renal function.
Hypertension 2002 Feb
PMID:Regulation of cyclooxygenase- and cytochrome p450-derived eicosanoids by heme oxygenase in the rat kidney. 1188 23

Modern methods of cell and molecular biology, augmented by molecular technology, have great potential for helping to unravel the complex mechanisms of various diseases. They also have the potential to help us try to dissect the events which follow the altered physiological conditions. Thus, there is every reason to believe that some of the potential mechanisms will be translated sooner or later into the clinic. Heme oxygenase (HO)-related mechanisms play an important role in several aspects of different diseases. In the past several years, significant progress has been made in our understanding of the function and regulation of HO. The objective of this article is to review current knowledge relating to the importance of HO mechanism in various diseases including myocardial ischemia/reperfusion, hypertension, cardiomyopathy, organ transplantation, endotoxemia, lung diseases, and immunosuppression. The morbidity and mortality of these diseases remain high even with optimal medical management. Furthermore, in this review, we consider various factors influencing the HO system and finally assess current pharmacological approaches to their control.
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PMID:The role of heme oxygenase signaling in various disorders. 1203 Mar 73

Heme plays a significant pathogenic role in several diseases involving the kidney. The cellular content of heme, derived either from the delivery of filtered heme proteins such as hemoglobin and myoglobin, or from the breakdown of ubiquitous intracellular heme proteins, is regulated via the heme oxygenase enzyme system. Heme oxygenases catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, which is subsequently converted to bilirubin by biliverdin reductase. Recent attention has focused on the biological effects of product(s) of this enzymatic reaction, which have important antioxidant, anti-inflammatory, and cytoprotective functions. Three isoforms of heme oxygenase (HO) enzyme have been described: an inducible isoform, HO-1, and two constitutively expressed isoforms, HO-2 and HO-3. Induction of HO-1 occurs as an adaptive and beneficial response to several injurious stimuli, and has been implicated in many clinically relevant disease states including atherosclerosis, transplant rejection, endotoxic shock, hypertension, acute lung injury, acute renal injury, as well as others. This review will focus predominantly on the role of HO-1 in the kidney.
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PMID:Heme oxygenase and the kidney. 1204 70

Heme oxygenase (HO) and carbon monoxide (CO) participate in the homeostatic control of cardiovascular functions, including the regulation of blood pressure (BP). Upregulation of the HO/CO system has been shown to lower BP in young (8 weeks) but not in adult (20 weeks) spontaneously hypertensive rats (SHR). The underlying mechanism for this selective effect, however, has been unknown and was investigated in the present study. The administration of hemin resulted in a marked decrease in BP (from 148.6+/-3.2 to 125.8+/-2.6 mm Hg, P<0.01) in young but not in prehypertensive (4 weeks) or adult SHR or Wistar-Kyoto rats at all ages. The inhibition of HO with chromium mesoporphyrin abrogated the BP-lowering effect of hemin. Significantly lower expression levels of HO-1 and soluble gyanylyl cyclase (sGC) as well as reduced cGMP content were detected in 8-week SHR but not in adult SHR or Wistar-Kyoto rats of all ages. These deficiencies were all corrected by hemin treatment. The expression of HO-2 protein was not different among all animal groups tested and not affected by hemin treatment. Desensitization of the sGC/cGMP pathway in adult SHR was demonstrated by the reduced vasorelaxant potency of the sGC activator 3-(5' -hydroxymethyl-2-'furyl)-1-benzylindazole. Thus, in young and prehypertensive SHR, a defective HO/CO-sGC/cGMP system might constitute a pathogenic mechanism for the development of hypertension. The HO/CO-sGC/cGMP system appears normal in adult SHR, but desensitization of the downstream targets of the system to sGC/cGMP may endow SHR at this stage a persistent hypertension status.
Hypertension 2002 Sep
PMID:Selective regulation of blood pressure by heme oxygenase-1 in hypertension. 1221 73

Heme oxygenase (HO) and carbon monoxide (CO) have been implicated in the modulation of various cardiovascular functions including blood pressure (BP) regulation. Up-regulating the HO/CO system lowers BP in young (8-week-old) but not in adult (20-week-old) spontaneously hypertensive rats (SHRs). The mechanisms for this selective effect are largely unknown. We investigated the effects of HO-1 inducer, hemin, on the HO/CO-soluble gyanylyl cyclase (sGC)/cGMP system in the aorta of prehypertensive (4-week-old) young and adult SHRs as well as age-matched Wistar-Kyoto rats (WKYs). Reduced expressions of HO-1, HO-2, and sGC proteins associated with depressed HO activity and cGMP levels were detected in young SHRs. These deficiencies were significantly reversed by hemin treatment. Macrophage infiltration of vascular tissues was more significant in adult SHRs than adult WKYs, but invisible in young SHRs and WKYs. Hemin treatment did not alter macrophage infiltration of vascular tissues in young SHRs. The same hemin administration resulted in a significant decrease in BP (from 148.6 +/- 3.2 to 125.8 +/- 2.6 mmHg, P <.01) in young SHRs, but not in prehypertensive or adult SHRs or WKYs of all ages. The HO inhibitor zinc protoporphyrin abrogated the hemin effect in young SHRs. Aortic tissues became desensitized to YC-1, an activator sGC, in adult SHRs. Thus, in young SHRs the expression and function of the HO/CO-sGC/cGMP system were suppressed, constituting a pathogenic mechanism for the development of hypertension. In adult SHRs, the HO/CO-sGC/cGMP system appeared normal, but desensitization of the sGC/cGMP pathway caused hypertension to prevail.
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PMID:Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats. 1250 17

Heme oxygenase (HO) regulates cellular heme levels and catalyzes the formation of bilirubin and carbon monoxide. We hypothesize that the status of the endothelial HO system influences the angiotensin (Ang) II-induced increase in the endothelial production of prostaglandin I2 (PGI2) (measured as 6-keto-PGF1alpha) and prostaglandin E2 (PGE2), eicosanoids that modulate the vascular actions of Ang II. In the present study, we determined the effect of interventions that suppress HO activity or induce HO-1 gene expression on Ang II-mediated increase in 6-keto-PGF1alpha and PGE2 in cultures of human femoral artery endothelial cells. Incubation of endothelial cells with Ang II (100 ng/mL) for 24 hours increased the levels of both 6-keto-PGF1alpha and PGE2 in the culture media. This effect of Ang II on prostaglandin production by endothelial cells was attenuated in cells treated with SnCl2 (10 micromol/L), an inducer of HO-1, but was magnified in cells treated with the HO inhibitor ZnDPP or heme. Upregulation of HO-1 gene expression by retrovirus-mediated delivery of the human HO-1 gene also attenuated heme and Ang II-induced prostaglandin synthesis. Of note, prostaglandin synthesis by lysates of endothelial cells stimulated with heme or Ang II appear to involve COX-2, because it was blunted by NS-398, which is presumed to inhibit COX-2 specifically. These results indicate that overexpression of the HO system exerts an inhibitory influence on Ang II-induced synthesis of prostaglandins by endothelial cells.
Hypertension 2003 Mar
PMID:Heme oxygenase attenuates angiotensin II-mediated increase in cyclooxygenase-2 activity in human femoral endothelial cells. 1262 85

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of the properties of inducible HO (HO-1) and its products, we hypothesized that HO-1 would play an important role in the regulation of cardiovascular function. In this article, we will review the role of HO-1 in the regulation of blood pressure and cardiac function and highlight previous studies from our laboratory using gene deletion and gene overexpression transgenic approaches in mice. These studies will include the investigation of HO-1 in the setting of hypertension (renovascular), hypotension (endotoxemia), and ischemia/reperfusion injury (heart). In a chronic renovascular hypertension model, hypertension, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney-one clip surgery were more severe in HO-1-null mice. In addition, HO-1-null mice with endotoxemia had earlier resolution of hypotension, yet the mortality and the incidence of end-organ damage were higher in the absence of HO-1. In contrast, mice with cardiac-specific overexpression of HO-1 had an improvement in cardiac function, smaller myocardial infarctions, and reduced inflammatory and oxidative damage after coronary artery ligation and reperfusion. Taken together, these studies suggest that an absence of HO-1 has detrimental consequences, whereas overexpression of HO-1 plays a protective role in hypoperfusion and ischemia/reperfusion injury.
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PMID:Role of heme oxygenase-1 in the regulation of blood pressure and cardiac function. 1270 67

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.
Hypertension 2003 Sep
PMID:Interaction of carbon monoxide and adenosine in the nucleus tractus solitarii of rats. 1291 65

Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Due to the properties of inducible HO (HO-1) and its products, we hypothesized that HO-1 would play an important role in the regulation of cardiovascular function. In this article we will review the role of HO-1 in cardiovascular function, and highlight our previous studies using gene deletion and gene overexpression transgenic approaches in mice. These studies will include the investigation of HO-1 in the setting of hypertension (renovascular), atherosclerosis and vascular injury (vein graft stenosis), hypotension (endotoxemia), and ischemia/reperfusion injury (heart). In a chronic renovascular hypertension model, blood pressure elevation, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney-one clip surgery are more severe in HO-1 null mice. Moreover, absence of HO-1 leads to accelerated atherosclerotic lesion formation and vein graft disease. In addition, HO-1 null mice with endotoxemia have earlier resolution of hypotension, yet the mortality and the incidence of end organ damage are higher in the absence of HO-1. In contrast, mice with cardiac-specific overexpression of HO-1 have an improvement in cardiac function, smaller myocardial infarcts, and reduced inflammatory and oxidative damage after coronary artery ligation and reperfusion. Taken together, these studies suggest that an absence of HO-1 has detrimental consequences, while overexpression of HO-1 plays a protective role in ischemia/reperfusion injury.
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PMID:Role of heme oxygenase-1 in cardiovascular function. 1452 47

We tested the hypothesis that the status of NO synthesis influences the renal heme-heme oxygenase system. Studies were conducted in untreated rats and rats treated with the NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester for 2 days. Treated and untreated rats were contrasted in terms of renal expression of heme oxygenase-1 and -2, renal carbon monoxide (CO)-generating activity, and urinary CO concentration and excretion rate. Heme oxygenase-1 and -2 proteins were similarly expressed in the kidneys of untreated and treated rats. In contrast, the NADPH-dependent component of the CO-generating activity of renal homogenates incubated with heme (a measure of heme oxygenase activity) was higher (P<0.05) in kidneys from rats treated with the NO synthesis inhibitor relative to corresponding data in untreated rats (1015+/-95 versus 379+/-111 pmol CO/mg per hour). Similarly, relative to corresponding data in untreated rats, rats treated with the NO synthesis inhibitor displayed increased (P<0.05) urinary CO concentration (920+/-174 versus 2286+/-472 pmol/mL) and urinary CO excretion (4.7+/-0.4 versus 14.3+/-2.7 pmol/min). This study demonstrates that NO synthesis inhibition upregulates the urinary concentration and excretion rate of CO, and the HO-dependent generation of CO by renal homogenates, without affecting the expression of renal heme oxygenase isoforms. Our findings imply that endogenous NO is an inhibitory regulator of renal CO generation by HO.
Hypertension 2004 Feb
PMID:Nitric oxide synthesis inhibition promotes renal production of carbon monoxide. 1469 98


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