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Biomedical subjects

Thomas Münzel

Publications and source records attributed to Thomas Münzel.

At least 37 records · Page 2Linked to original sources
PubMed2005

Mechanisms of increased vascular superoxide production in an experimental model of idiopathic dilated cardiomyopathy.

OBJECTIVE: In the present study, we sought to identify mechanisms underlying increased oxidative stress in vascular tissue in an experimental animal model of chronic congestive heart failure (CHF). METHODS AND RESULTS: Superoxide and nitric oxide (NO) was measured in vessels from cardiomyopathic hamsters (CHF hamsters) and golden Syrian hamsters. We also determined expression of endothelial nitric oxide synthase (NOSIII), the soluble guanylyl cyclase, the cGMP-dependent kinase, and the NADPH oxidase. To analyze the contribution of the renin-angiotensin system to oxidative stress, CHF hamsters were treated with the angiotensin-converting enzyme inhibitor captopril for 200 days (120 mg . kg(-1) . d(-1)). CHF led to increased superoxide production by NOSIII and the NADPH oxidase. Decreased NO production in CHF was associated with a decrease in the expression of NOSIII and an inhibition of NO downstream signaling in the aorta. NOSIII expression was increased within the left ventricle. Captopril treatment normalized NOSIII expression in vessels and the myocardium, reduced superoxide levels, and prevented NOSIII uncoupling. Accordingly, endothelial function, NO production, and downstream signaling were improved in CHF vessels. CONCLUSIONS: Oxidative stress in CHF is mediated by NADPH oxidase and an uncoupled NOSIII secondary to an activation of the renin-angiotensin system leading to impaired NO downstream signaling.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Explaining the phenomenon of nitrate tolerance.

During the last century, nitroglycerin has been the most commonly used antiischemic and antianginal agent. Unfortunately, after continuous application, its therapeutic efficacy rapidly vanishes. Neurohormonal activation of vasoconstrictor signals and intravascular volume expansion constitute early counter-regulatory responses (pseudotolerance), whereas long-term treatment induces intrinsic vascular changes, eg, a loss of nitrovasodilator-responsiveness (vascular tolerance). This is caused by increased vascular superoxide production and a supersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. NADPH oxidase(s) and uncoupled endothelial nitric oxide synthase have been proposed as superoxide sources. Superoxide and vascular NO rapidly form peroxynitrite, which aggravates tolerance by promoting NO synthase uncoupling and inhibition of soluble guanylyl cyclase and prostacyclin synthase. This oxidative stress concept may explain why radical scavengers and substances, which reduce oxidative stress indirectly, are able to relieve tolerance and endothelial dysfunction. Recent work has defined a new tolerance mechanism, ie, an inhibition of mitochondrial aldehyde dehydrogenase, the enzyme that accomplishes bioactivation of nitroglycerin, and has identified mitochondria as an additional source of reactive oxygen species. Nitroglycerin-induced reactive oxygen species inhibit the bioactivation of nitroglycerin by thiol oxidation of aldehyde dehydrogenase. Both mechanisms, increased oxidative stress and impaired bioactivation of nitroglycerin, can be joined to provide a new concept for nitroglycerin tolerance and cross-tolerance. The consequences of these processes for the nitroglycerin downstream targets soluble guanylyl cyclase, cGMP-dependent protein kinase, cGMP-degrading phosphodiesterases, and toxic side effects contributing to endothelial dysfunction, such as inhibition of prostacyclin synthase, are discussed in this review.

Aldehyde Dehydrogenase↗
PubMed2005

Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study.

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6+/-1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 micromol/L; P<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (P for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06; P<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0; P=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8; P=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.

Adult↗
PubMed2005

Oxypurinol improves coronary and peripheral endothelial function in patients with coronary artery disease.

Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.

Aged↗
PubMed2005

The oxidative stress concept of nitrate tolerance and the antioxidant properties of hydralazine.

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted as a result of the development of nitrate tolerance. With initiation of NTG therapy, it is possible to detect neurohormonal activation and intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise the vasodilatory effects of NTG. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide (O2-) production and an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C contribute to the development of tolerance. Nicotinamide adenine dinucleotide phosphate oxidase and the uncoupled endothelial nitric oxide synthase may be O2- -producing enzymes. Nitric oxide (NO) and O2-, both derived from NTG and the vessel wall, form peroxynitrite in a diffusion-limited rapid reaction. Peroxynitrite, O2-, or both may be responsible for the development of nitrate tolerance and cross-tolerance to direct NO donors (eg, sodium nitroprusside, sydnonimines) and endothelium-dependent NO synthase-activating vasodilators. Hydralazine is an efficient reactive oxygen species (ROS) scavenger and an inhibitor of O2- generation. When given concomitantly with NTG, hydralazine prevents the development of nitrate tolerance and normalizes endogenous rates of vascular O2- production. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates NTG (ie, mitochondrial aldehyde dehydrogenase isoform 2 [ALDH2]) and mitochondria as potential sources of ROS. NTG-induced ROS inhibit the bioactivation of NTG by ALDH2. Both mechanisms increase oxidative stress and impair NTG bioactivation, and now converge at the level of ALDH2 to support a new theory for NTG tolerance and NTG-induced endothelial dysfunction. The consequences of these processes for NTG downstream targets (eg, soluble guanylyl cyclase, cyclic guanosine monophosphate-dependent protein kinase), toxic effects contributing to endothelial dysfunction (eg, prostacyclin synthase inhibition) and novel applications of the antioxidant properties of hydralazine are discussed.

Animals↗
PubMed2005

Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease.

BACKGROUND: Interleukin (IL)-18 plays a key role in atherosclerosis and its complications. The present study investigated the genetic variability of 4 genes of the IL-18 system-IL18, IL18R1, IL18RAP, and IL18BP-in relation to circulating IL-18 levels and cardiovascular mortality. METHODS AND RESULTS: Twenty-two polymorphisms were genotyped in 1288 patients with coronary artery disease prospectively followed up during a median period of 5.9 years. The end point was death from cardiovascular causes (n=142). Baseline IL-18 levels were predictive of cardiovascular deaths occurring during < or =4 years of follow-up (HR=2.96, 95% CI 1.54 to 5.70, P=0.001 for the top compared with the bottom quartile) but not of later deaths. Haplotypes of the IL18 gene were associated with IL-18 levels (P=0.002) and cardiovascular mortality (P=0.006) after adjustment for cardiovascular risk factors. The same haplotype was associated with both a 9% lowering effect on IL-18 levels and a protective effect on risk (HR=0.57, 95% CI 0.36 to 0.92). IL18 haplotypes explained only 2% of IL-18 variability. Adjustment for baseline IL-18 levels abolished the association of haplotypes with cardiovascular risk. The haplotype associated with phenotypes was the only one carrying the minor allele of the IL18/A+183G polymorphism located in the 3'untranslated region and potentially affecting mRNA stability. The other genes of the system were not related to IL-18 levels or cardiovascular outcome. CONCLUSIONS: Variations of the IL18 gene consistently influence circulating levels of IL-18 and clinical outcome in patients with coronary artery disease, which supports the hypothesis of a causal role of IL-18 in atherosclerosis and its complications.

Cardiovascular Diseases↗
PubMed2005

Heterozygous deficiency of manganese superoxide dismutase in mice (Mn-SOD+/-): a novel approach to assess the role of oxidative stress for the development of nitrate tolerance.

Nitroglycerin (GTN)-induced tolerance was reported to be associated with increased levels of reactive oxygen species (ROS) in mitochondria. In the present study, we further investigated the role of ROS for the development of nitrate tolerance by using heterozygous manganese superoxide dismutase knock-out mice (Mn-SOD+/-). Mn-SOD is acknowledged as a major sink for mitochondrial superoxide. Vasodilator potency of mouse aorta in response to acetylcholine and GTN was assessed by isometric tension studies. Mitochondrial ROS formation was detected by 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt (L-012)-enhanced chemiluminescence and mitochondrial aldehyde dehydrogenase (ALDH-2) activity was determined by a high-performance liquid chromatography-based assay. Aortic rings from Mn-SOD+/- mice showed normal endothelial function and vasodilator responses to GTN. In contrast, preincubation of aorta with GTN or long-term GTN infusion caused a marked higher degree of tolerance as well as endothelial dysfunction in Mn-SOD+/- compared with wild type. Basal as well as GTN-stimulated ROS formation was significantly increased in isolated heart mitochondria from Mn-SOD+/- mice, correlating well with a marked decrease in ALDH-2 activity in response to in vitro and in vivo GTN treatment. The data presented indicate that deficiency in Mn-SOD leads to a higher degree of tolerance and endothelial dysfunction associated with increased mitochondrial ROS production in response to in vitro and in vivo GTN challenges. These data further point to a crucial role of ALDH-2 in mediating GTN bioactivation as well as development of GTN tolerance and underline the important contribution of ROS to these processes.

Aldehyde Dehydrogenase↗
PubMed2005

Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase.

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxide-producing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases.

Animals↗
PubMed2005

Glutathione peroxidase-1 and homocysteine for cardiovascular risk prediction: results from the AtheroGene study.

OBJECTIVES: This prospective study was designed to evaluate the effect of joint determination of two important contrary biomarkers--homocysteine and glutathione peroxidase (GPx)-1--on cardiovascular risk stratification. BACKGROUND: Homocysteine plasma levels have been associated with cardiovascular risk. Experimental data suggest that antioxidative GPx-1 activity modulates cardiovascular risk associated with homocysteine. METHODS: In 643 patients with coronary artery disease, we performed a prospective study to assess the risk of homocysteine plasma levels and GPx-1 activity on long-term cardiovascular risk with a median follow-up of 7.1 years. RESULTS: Both homocysteine and GPx-1 were among the strongest univariate predictors of future cardiovascular risk, even after adjustment for cardiovascular confounders. Homocysteine levels were significantly elevated in individuals with future cardiovascular events (15.4 vs. 13.4 micromol/l; p < 0.0001); GPx-1 activity was lower (45.3 +/- 13.1 vs. 50.2 +/- 11.0 U/g hemoglobin; p < 0.0001). In patients with GPx-1 activity below the median value, homocysteine plasma levels above the median were associated with a 3.2-fold (95% confidence interval 1.8 to 5.6; p < 0.0001) increase in cardiovascular risk, whereas it lost its independent risk prediction in individuals with increased antioxidative capacity, as reflected by high GPx-1 activity. In contrast to single determination, combined assessment revealed a significant increase in the area under the curve of cardiovascular risk predictive models from 0.72, including traditional risk factors to 0.75 and also including homocysteine levels and GPx-1 activity. CONCLUSIONS: Plasma homocysteine levels and GPx-1 activity are complementary in identifying individuals at high cardiovascular risk. Joint determination of both biomarkers provides substantial information on top of classic risk factors in cardiovascular risk assessment.

Aged↗
PubMed2005

Differential effects of diabetes on the expression of the gp91phox homologues nox1 and nox4.

The nox2-dependent NADPH oxidase was shown to be a major superoxide source in vascular disease, including diabetes. Smooth muscle cells of large arteries lack the phagocytic gp91phox subunit of the enzyme; however, two homologues have been identified in these cells, nox1 and nox4. It remained to be established whether also increases in protein levels of the nonphagocytic NADPH oxidase contribute to increased superoxide formation in diabetic vessels. To investigate changes in the expression of these homologues, we measured their expression in aortic vessels of type I diabetic rats. Eight weeks after streptozotocin treatment, we found a doubling in nox1 protein expression, while the expression of nox4 remained unchanged. This was associated with a significant increase in the NADPH oxidase activity in membrane fractions of diabetic heart and aortic tissue. Furthermore, we observed a decreased sensitivity of diabetic vessels to acetylcholine and nitroglycerin and a decrease in both acetylcholine-stimulated NO production and phosphorylation of VASP, despite an increase in endothelial NO synthase (NOSIII) expression. In addition, xanthine oxidase activity was markedly increased in plasma and 100,000 g supernatant of cardiac tissue of diabetic rats, while myocardial mitochondrial superoxide formation was only weakly enhanced. We conclude that in addition to phagocytic NADPH oxidase, also nonphagocytic, vascular NADPH oxidase subunit nox1, uncoupled NOSIII, and plasma xanthine oxidase contribute to endothelial dysfunction in the setting of diabetes mellitus.

Acetylcholine↗
PubMed2005

Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis.

OBJECTIVE: Sedentary lifestyle is associated with increased cardiovascular events. The underlying molecular mechanisms are incompletely understood. Reactive oxygen species (ROS) contribute to endothelial dysfunction and atherosclerosis. An important source of vascular ROS is the NADPH oxidase. METHODS AND RESULTS: C57BL6 mice were subjected to regular housing (physical inactivity) or voluntary training on running wheels (6 weeks). Inactivity increased vascular lipid peroxidation to 148+/-9% and upregulated superoxide release to 176+/-17% (L-012 chemiluminescence) and 188+/-29% (cytochrome C reduction assay), respectively. ROS production was predominantly increased in the endothelium and the media (dihydroethidium fluorescence). Activity of the NADPH oxidase was increased to 154+/-22% in the sedentary group. Rac1 GST-PAK pull-down assays showed an upregulation of rac1 activity to 161+/-14%. Expression levels of the subunits nox1, p47phox, and p67phox were increased. To address the significance of the antioxidative effects of running, experiments were repeated in apolipoprotein E-deficient mice treated with a high-cholesterol diet. Inactivity increased vascular superoxide production and impaired endothelium-dependent vasorelaxation. Atherosclerotic lesion formation was significantly accelerated in sedentary mice. CONCLUSIONS: Inactivity increases vascular NADPH oxidase expression and activity and enhances vascular ROS production, which contributes to endothelial dysfunction and atherosclerosis during sedentary as opposed to physically active lifestyle.

Animals↗
PubMed2005

Prolonged recirculation is required to detect secondary metabolic and hemodynamic deterioration after superior mesenteric artery occlusion.

We evaluated late (4 hrs) effects of reperfusion on hemodynamics after 30 or 60 min occlusion of the superior mesenteric artery (SMA) in a rat model. Spontaneously breathing animals (n=30) underwent occlusion of the SMA for 0 (sham), 30 (SMAO_30) or 60 min (SMAO_60) followed by reperfusion with normal saline. Abdominal blood flow (ABF), SMA blood flow (SBF), arterial blood pressure and heart rate were recorded continuously. Systemic vascular resistance (SVR) and SMA vascular resistance (MVR) were calculated at baseline and after 240 min reperfusion (240R). All animals survived in SMAO_30 and sham, two died in SMAO_60 after 120R. ABF remained constant in all groups. SVR increased in SMAO_30 and sham and decreased in SMAO_60 at 240R. SBF was significantly lower after reperfusion in ischemia groups as compared to sham. After 120R, SBF had increased significantly in SMAO_60 versus SMAO_30. MVR increased significantly in SMAO_30 but not in SMAO_60 and sham at 240R. 60 minutes SMA occlusion revealed early hemodynamic changes of septic circulation with increased blood flow in the SMA, decreased SVR, and pseudo-normalization of MVR. Prolonged observation periods are required to detect these significant changes which are overlooked when only studying 120 minutes of reperfusion as usually done.

Abdomen↗
PubMed2004

Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins.

Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with healthy individuals. Isolated PMNs bound free MPO by a CD11b/CD18 integrin-dependent mechanism. PMNs exposed to MPO were characterized by increased tyrosine phosphorylation and p38 mitogen-activated protein kinase activation. Also, nuclear translocation of NFkappaBin PMN was enhanced after incubation with MPO, as was surface expression of CD11b. Binding of PMN to MPO-coated fibronectin surfaces amplified PMN degranulation, as evidenced by increased release of MPO and elastase. MPO also augmented PMN-dependent superoxide (O(2)(*-)) production, which was prevented by anti-CD11b antibodies, but not MPO inhibitors. Collectively, these results reveal that binding of MPO to CD11b/CD18 integrins stimulates PMN signaling pathways to induce PMN activation in a mechanism independent of MPO catalytic activity. These cytokine-like properties of MPO thus represent an additional dimension of the proinflammatory actions of MPO in vascular disease.

CD11b Antigen↗
PubMed2004

Analysis of N-terminal-pro-brain natriuretic peptide and C-reactive protein for risk stratification in stable and unstable coronary artery disease: results from the AtheroGene study.

AIMS: N-terminal-pro-brain natriuretic peptide (Nt-proBNP) is a reliable risk predictor in acute coronary artery disease (CAD). Little is known about patients with stable angina pectoris (SAP). We aimed to investigate the prognostic impact of Nt-proBNP in a population with CAD especially focussing on patients with SAP. METHODS AND RESULTS: We obtained baseline samples from a prospective cohort of 904 consecutive patients with CAD. Cardiovascular events were registered during follow-up (median 2 years; maximum 3.7 years). Baseline Nt-proBNP was significantly higher among individuals with cardiovascular events compared with those without (711.5 vs. 238.8 pg/mL; P<0.0001). A similar association was found if the analysis was performed in patients who presented with stable angina (330 vs. 166.5 pg/mL; P=0.006) or acute coronary syndrome (990.9 vs. 527.7 pg/mL; P=0.03). In the SAP group, patients within the top quartile (>487.9 pg/mL) had a 3.7-fold (95% CI 1.2-9.1; P=0.01) increase in cardiovascular risk. After adjustment for most potential confounders including left ventricular ejection fraction, Nt-proBNP remained predictive for patients with serum concentrations in the upper quartile in comparison with patients in the lowest quartile (hazard ratio highest vs. lowest quartile: 4.0; P=0.03) (n=417). CONCLUSION: Baseline concentration of Nt-proBNP is independently related to future cardiovascular events in patients with stable angina.

Angina Pectoris↗
PubMed2004

Myeloperoxidase enhances nitric oxide catabolism during myocardial ischemia and reperfusion.

Impaired microvascular function during myocardial ischemia and reperfusion is associated with recruitment of polymorphonuclear neutrophils (PMN) and has been attributed to decreased bioavailability of nitric oxide (NO). Whereas myeloperoxidase (MPO), a highly abundant, PMN-derived heme protein facilitates oxidative NO consumption and impairs vascular function in animal models of acute inflammation, its capacity to function in this regard during human myocardial ischemia and reperfusion remains unknown. Plasma samples from 30 consecutive patients (61 +/- 14 years, 80% male) presenting with acute myocardial infarction were collected 9 +/- 4 h after vessel recanalization and compared to plasma from healthy control subjects (n = 12). Plasma levels of MPO were higher in patients than in control subjects (1.4 +/- 0.9 vs 0.3 +/- 0.2 ng/mg protein, respectively, p < 0.0001). The addition of hydrogen peroxide to patient plasma resulted in accelerated rates of NO consumption compared to control subjects (0.53 +/- 0.25 vs 0.068 +/- 0.039 nM/s/mg protein, respectively, p < 0.0001). Myocardial tissue from patients with the same pathology revealed intense recruitment of MPO-positive PMN localized along infarct-related vessels as well as diffuse endothelial distribution of non-PMN-associated MPO immunoreactivity. Endothelium-dependent microvascular function, as assessed by an acetylcholine-dependent increase in forearm blood flow in 75 patients with symptomatic coronary artery disease, inversely correlated with MPO plasma levels (r = -0.75, p < 0.005). Plasma from patients undergoing myocardial reperfusion contained increased levels of MPO, which catalytically consumed NO in the presence of H(2)O(2). Given the correlation between intravascular MPO levels and forearm vasomotor function in patients with coronary artery disease, MPO appears to be an important modulator of vasomotor function in inflammatory vascular disease and a potential therapeutic target for treatment.

Aged↗
PubMed2004

Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates.

Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN- and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations >1 microM. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.

Aldehyde Dehydrogenase↗