Plasma Heme Oxygenase-1 Research Articles

Plasma heme oxygenase-1 is decreased in peripheral artery disease patients.

Peripheral artery disease (PAD) is a common manifestation of atherosclerosis. A number of emerging risk factors, including oxidative stress biomarkers, free radicals and heat shock proteins, may add to the established risk factors for cardiovascular disease (CVD). The present study assessed surrogate markers of oxidative stress, including total reduced glutathione (GSH), lipid hydroperoxides (LOOH), isoprostanes, heme oxygenase‑1 (HO‑1) and metabolic biomarkers, such as adiponectin and lactate, in PAD patients (n=27). Healthy age‑matched volunteers (n=27) served as controls. GSH and LOOH were evaluated by measuring total thiol groups and iron oxidation, respectively, by spectrophotometric analysis. Adiponectin, isoprostanes and HO‑1 levels were determined using commercially available ELISA kits and lactate level was determined colorimetrically. Results from patients with PAD demonstrated no significant difference in GSH content and LOOH formation when compared with healthy controls (5.1±7.6vs.6.9±9.1nmol/ml and 6.8±14.2vs.8.3±14.9nmol/ml, respectively), however, isoprostanes were demonstrated to be significantly reduced (3.8±4.8pg/mlvs.120±91pg/mll; P<0.001). Furthermore, HO‑1, a protective heat shock protein, was significantly reduced in PAD patients (0.8±0.7vs.3.4±1.3ng/ml; P<0.001). Adiponectin, an antiatherogenic adipokine, was not significantly different between the two groups (1.4±0.2vs.1.5±0.5µg/ml), whereas serum lactate was significantly higher in PAD patients compared with controls (0.11±0.01vs.0.1±0.01mM; P<0.05). Using multivariate analysis, HO‑1, hypertension, smoking and dyslipidemia were indicated to be independently associated with the presence of PAD, while only ankle‑brachial index was an independent predictor of severity of PAD. The oxidative pathway may be partially involved in the onset and progression of PAD and may represent a target to reduce the risk of ischemic events.

Increased Plasma Levels of Heme Oxygenase-1 in Human Brucellosis.

Brucellosis is associated with inflammation and the oxidative stress response. Heme oxygenase-1 (HO-1) is a cytoprotective stress-responsive enzyme that has anti-inflammatory and anti-oxidant effects. Nevertheless, the role of HO-1 in human brucellosis has not yet been studied. The aim of this study was to examine the plasma levels of HO-1 in patients with brucellosis and to evaluate the ability of plasma HO-1 levels as an auxiliary diagnosis, a severity predictor, and a monitor for brucellosis treatments. A total of 75 patients with brucellosis were divided into the acute, subacute, chronic active, and chronic stable groups. An additional 20 volunteers were included as the healthy control group. The plasma HO-1 levels and other laboratory parameters were measured in all groups. Furthermore, the plasma levels of HO-1 in the acute group were compared before and after treatment. The plasma HO-1 levels were considerably increased in the acute (4.97 ± 3.55), subacute (4.98 ± 3.23), and chronic active groups (4.43 ± 3.00) with brucellosis compared to the healthy control group (1.03 ± 0.63) (p < 0.01). In the acute group, the plasma HO-1 levels in the post-treatment group (2.33 ± 2.39) were significantly reduced compared to the pre-treatment group (4.97 ± 3.55) (p < 0.01). On the other hand, the plasma HO-1 levels were higher in the chronic active group (4.43 ± 3.00) than the chronic stable group (2.74 ± 2.23) (p < 0.05). However, the plasma HO-1 levels in the chronic stable group (2.74 ± 2.23) remained higher than the levels in the healthy control group (1.03 ± 0.63) (p < 0.05). The HO-1 levels were positively correlated with the C-reactive protein (CRP) levels in patients with brucellosis (r = 0.707, p < 0.01). The plasma HO-1 levels can reflect patients' brucellosis status and may be used as a supplementary plasma marker for diagnosing brucellosis and monitoring its treatment.

Upregulation of Heme Oxygenase-1 in Response to Wild Thyme Treatment Protects against Hypertension and Oxidative Stress.

High blood pressure is the most powerful contributor to the cardiovascular morbidity and mortality, and inverse correlation between consumption of polyphenol-rich foods or beverages and incidence of cardiovascular diseases gains more importance. Reactive oxygen species plays an important role in the development of hypertension. We found that wild thyme (a spice plant, rich in polyphenolic compounds) induced a significant decrease of blood pressure and vascular resistance in hypertensive rats. The inverse correlation between vascular resistance and plasma heme oxygenase-1 suggests that endogenous vasodilator carbon monoxide generated by heme oxidation could account for this normalization of blood pressure. Next product of heme oxidation, bilirubin (a chain-breaking antioxidant that acts as a lipid peroxyl radical scavenger), becomes significantly increased after wild thyme treatment and induces the reduction of plasma lipid peroxidation in hypertensive, but not in normotensive rats. The obtained results promote wild thyme as useful supplement for cardiovascular interventions.

Targeted Disruption of Nrf2 in Non-Hematopoietic Tissues Exacerbates Hemolysis and Accelerates Chronic Lung Disease in Transgenic Sickle Cell Anemia Mice

Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates the cellular defense mechanism by mediating a coordinate induction of cytoprotective antioxidant responsive element-driven genes. Nrf2 agonists augment fetal hemoglobin expression in hematopoietic progenitors and have emerged as a new class of drugs for therapeutic induction of fetal hemoglobin in sickle cell anemia (SCA). However, the cytoprotective effect of Nrf2 on the pathobiology of SCA has not been previously defined. To investigate the role and mechanism of Nrf2 in SCA independent of globin gene modulation, we generated chimeric mice with disruption of Nrf2 in non-hematopoietic tissues. A total of twenty-six Nrf2-/- mice were transplanted with bone marrow harvested from the Berkeley sickle and hemizygous (Hemi) mice and the Townes sickle (SS) and control (AA) mice. All sickle/Nrf2-null chimeras (SSNHNrf2-/-; n=13) developed classical hematological and intravascular hemolysis features of SCA after eight weeks of transplantation. Despite the presence of erythrocyte Nrf2, SSNHNrf2-/- chimeras developed more severe intravascular hemolysis than SS wild-type (SSWT) donor-litter-mates. The concentration of plasma cell-free Hb (p<0.01), plasma heme (p<0.05) and lactate dehydrogenase (p<0.05) were 1.5 to 2.0-fold higher in the chimeras than in the SSWT mice. The chimeras had markedly higher concentrations of soluble vascular cell adhesion molecule-1 (p<0.01) and soluble P-selectin in their plasma (p<0.05), and more oxidizing extracellular redox status (p<0.05). The latter finding was corroborated by markedly lower reduced-glutathione in the SSNHNrf2-/- mouse lungs (19.07±0.32 vs 26.5 ±1.5 nmol/mg protein, p<0.01). The worsening of hemolysis, vascular inflammation and oxidative stress in the SSNHNrf2-/- chimeras was unrelated to the transplantation procedure since none of these effects were seen in the AANHNrf2-/- and HemiNHNrf2-/- controls. Next, we found that the SSNHNrf2-/- chimeras had hypoxemia at baseline (oxygen saturation, 95.8±1.7%) while age-matched SSWT mice had normal oxygen saturation (99.2±0.2%, p<0.05). Consistent with these disparate pulmonary phenotypes, the SSNHNrf2-/- but not the SSWT mice developed pulmonary edema at a relatively young age, which was confirmed by histological evidence of alveolar edema. Remarkably, the severely damaged SSNHNrf2-/- mouse lungs contained a similar quantity of heme oxygenase-1 (HO-1) mRNA and protein as the relatively less inflamed SSWT lungs. In addition, the amount of HO-1 in the plasma was also similar in these animals. These results indicate that other transcription factors modulate HO-1 induction, and that HO-1 may play a lesser role in mitigating the chronic effects of SCA. To test the latter idea, we performed a longitudinal study in a cohort of thirty-two SS and AA mice of both sexes. At 8 weeks of age, plasma HO-1 was 3-fold higher in both male and female SS mice than in the AA mice (p<0.001). The HO-1 values did not change at 12, 24 and 40 weeks in any group, however intravascular hemolysis, vascular inflammation and endothelial barrier integrity deteriorated progressively only in the SSWT mice. Overall, our results demonstrate that the elevated HO-1 expression typical of SCA is insufficient to blunt many of the chronic effects of the disease in mice. However, other Nrf2 target genes in non-hematopoietic tissues can slow down this process. Such genes offer an attractive prophylactic therapeutic strategy to preserve organ function in adults with SCA. DisclosuresArcher:Global Blood Therapeutics: Consultancy.

Heme oxygenase-1 induction by cobalt protoporphyrin enhances fever and inhibits pyrogenic tolerance to lipopolysaccharide

Heme oxygenase-1 (HO-1) is an enzyme that catalyzes degradation of the heme and regulates its availability for newly synthetized hemeproteins such as cyclooxygenases, NO synthases and cytochrome P450. Moreover, HO-1 activity modulates synthesis of cytokines and prostaglandins. All of these factors are well-defined components of fever and pyrogenic tolerance mechanisms. We examine the effect of HO-1 induction and activation using cobalt protoporphyrin (CoPP) on changes in body temperature (Tb), plasma levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and HO-1 protein in the course of these processes. Intraperitoneally (i.p.) pre-treatment of rats with CoPP (5mgkg−1) significantly accelerated and enhanced the early stage of lipopolysaccharide (LPS)-induced fever and shortened a post-fever recovery to normal temperature. Pre-treatment with CoPP significantly potentiated the increase in plasma IL-6, PGE2 and HO-1 levels measured 4h after the LPS administration. Furthermore, induction of HO-1 attenuated the development of pyrogenic tolerance to repeated injections of LPS. Based on these data we conclude that heme oxygenase-1 may act as a physiological regulator of the febrile response intensity to bacterial infections.

Effects of aspirin & simvastatin and aspirin, simvastatin, & lipoic acid on heme oxygenase-1 in healthy human subjects.

Heme oxygenase 1 (HO-1) degrades heme and protects against oxidative stress. In vitro and animal models suggest that HO-1 is beneficial in several diseases (e.g., postoperative ileus, gastroparesis, acute pancreatitis, and colitis). However, the only drugs (i.e., hemin and heme arginate) which pharmacologically upregulate HO-1 in humans are expensive and can only be administered intravenously. Our aims were to compare the effects of placebo, aspirin, and simvastatin alone, and with α-lipoic acid, on HO-1 protein concentration and activity in humans. This randomized, double-blind, placebo-controlled study compared the effects of three oral regimens administered for 7days, i.e., placebo; aspirin (325mg twice daily) and simvastatin (40mg twice daily); aspirin, simvastatin, and the sodium salt of R- α-lipoic acid (NaRLA, 600mg three times daily) on markers of HO-1 activation (i.e., plasma HO-1 protein concentration and venous monocyte HO-1 protein activity) in 18 healthy subjects (14 females). Markers of HO-1 activation were evaluated at baseline, days 2, and 7. Baseline HO-1 protein concentrations and activity were similar among the three groups. Compared to placebo, aspirin and simvastatin combined, or together with NaRLA did not affect HO-1 protein concentration or activity at 2 or 7days. HO-1 protein concentrations and activity were correlated on day 7 (r=0.75, p=0.0004) but not at baseline and on day 2. At therapeutic doses, aspirin, simvastatin, and α-lipoic acid do not increase plasma HO-1 protein concentration or venous monocyte HO-1 activity in healthy humans.

P171Elevated free fetal haemoglobin threatens vasculoprotection in the fetal circulation of preeclamptic pregnancy

Placental up-regulation of free fetal haemoglobin (fHbF) occurs in preeclamptic (PE) pregnancy. Heme oxygenase-1 (HO-1) is an important vasculoprotective enzyme in the catabolism of the associated heme porphyrin structure. We have previously shown that fHbF negatively influences the vasculoprotective capacity of the fetal circulation. Here we study fHbF levels in the fetal cord blood of pregnancies complicated by PE; a pathology associated with dysregulated fetoplacental vascular tone. We have previously shown that fHbF binds nitric oxide (NO) to elicit elevated vascular resistance in the fetoplacental circulation, using ex vivo human dual placental perfusion and in vitro placental endothelial cell shear stress studies. Furthermore, fHbF causes morphological changes to the fetoplacental endothelium. Here we hypothesise that elevated levels of fHbF in fetal plasma associated with placental pathology contribute to fetoplacental hypertension. Purpose: To evaluate and derive a robust cord blood collection and processing protocol for the accurate measurement of fetal plasma fHbF levels in normal and PE pregnancies. Methods: Fetal venous cord blood was collected by syringe and needle, or Vacutainer method into either EDTA or citrate tubes, within 10 minutes of partum. Plasma recovery occurred immediately, or after 30 minutes, prior to centrifugation at 2000g x 10 min at room temperature. Following evaluation to reduce mechanical haemolysis, newly collected normal & PE plasma (n=13 & 6, respectively) was subjected to ELISAs for HbF and HO-1. Results: Venipuncture collection of cord venous blood taken from the cord-placenta insertion point by Vacutainer system with a 21G needle, into citrate collection tubes with immediate centrifugation prevented mechanical haemolysis. There was no difference in plasma HO-1 between groups (medians = 5.9 & 5.3 ng/mL; normal & PE, respectively; Mann-Whitney). Whilst there was no difference in fHbF between groups (Mann-Whitney), variability was high in the PE group and there were some very high values for fHbF compared to the normal range, whilst fHbF values in the control group were within a tighter lower range (medians & ranges = 45.9 & 0-206 and 118.8 & 29-640 μg/mL). Conclusion: Fetal plasma HO-1 levels appear stable in preeclamptic fetal plasma, permitting fHbF to remain unchecked in some cases. High pathophysiological levels of fHbF in some cases of PE pregnancies are capable of evoking elevated vascular resistance within the fetoplacental circulation, caused by nitric oxide sequestration and disruption to the endothelium. Further evaluation is required.

Heme Oxygenase-1 and Acute Kidney Injury following Cardiac Surgery

Background: Intraoperative hemolysis and inflammation are associated with acute kidney injury (AKI) following cardiac surgery. Plasma-free hemoglobin induces heme oxygenase-1 (HO-1) expression. HO-1 degrades heme but increases in experimental models of AKI. This study tested the hypothesis that plasma HO-1 concentrations are associated with intraoperative hemolysis and are increased in patients that develop AKI following cardiac surgery. Methods: We measured plasma HO-1, free hemoglobin, and inflammatory markers in 74 patients undergoing cardiopulmonary bypass (CPB). AKI was defined as an increase in serum creatinine concentration of 50% or 0.3 mg/dl within 72 h of surgery. Results: Twenty-eight percent of patients developed AKI. HO-1 concentrations increased from 4.2 ± 0.2 ng/ml at baseline to 6.6 ± 0.5 ng/ml on postoperative day (POD) 1 (p < 0.001). POD1 HO-1 concentrations were 3.1 ng/ml higher (95% CI 1.1-5.1) in AKI patients, as was the change in HO-1 from baseline to POD1 (4.4 ± 1.3 ng/ml in AKI patients vs. 1.5 ± 0.3 ng/ml in no-AKI patients, p = 0.006). HO-1 concentrations remained elevated in AKI patients even after controlling for AKI risk factors and preoperative drug therapy. Peak-free hemoglobin concentrations correlated with peak HO-1 concentrations on POD1 in patients that developed AKI (p = 0.02). Duration of CPB and post-CPB IL-6 and IL-10 concentrations were also associated with increased HO-1 on POD1. Conclusion: Plasma HO-1 is increased in patients that develop AKI, and CPB duration, hemolysis, and inflammation are associated with increased HO-1 concentrations following cardiac surgery. Strategies that alter hemolysis and HO-1 expression during cardiac surgery may affect risk for AKI.

Determinants Of Heme-Oxygenase-1 Upregulation In Patients With Sickle Cell Disease

Inflammation is a cardinal component of the pathogenesis of sickle cell disease (SCD). Increased plasma concentration of the inflammatory agonist hemin increases the odds of acute chest syndrome (ACS) in children with SCD (Adisa et al., Br. J Haematol, 2013). In addition, free hemin promotes the development of a lethal ACS-like disease in transgenic sickle mice (Ghosh et al., J Clin Invest, 2013). Hemin degradation is controlled by the rate-limiting enzyme heme oxygenase-1 (HO-1). Polymorphism of a (GT)n dinucleotide repeat in the HO-1 promoter, which enhances expression of the gene, is associated with lower rates of hospitalization for ACS in children. Over-expression of HO-1 reduces stasis in a mouse model of SCD vaso-occlusion. However, the role of plasma HO-1 in SCD patients is entirely unknown. In this study, we measured steady-state plasma HO-1 in two cohorts of patients. Cohort 1 in Atlanta (n=98) consisted of children with a mean age of 10.07±0.42 years (range 2-19 years) and cohort 2 from Accra (n=80) consisted of older patients (mean age 25.30±1.0 years, range 13-58 years). The mean plasma HO-1 of both cohorts was significantly higher compared to the mean value of age- and ethnic-matched individuals with normal adult Hb; Atlanta: 10.19±5.80 vs. 2.08± 1.16, p<0.0001 and Accra: 13.7±8.14 vs. 2.57± 0.82, p<0.0001. Plasma HO-1 varied by 25-fold in both cohorts and it correlated with the white blood cell count (Atlanta: r=0.3361, p<0.0001, Accra: r=0.25, p=0.02). Fifty-four percent (n=53) of subjects in the Atlanta cohort were on hydroxyurea. The mean plasma HO-1 of this subgroup was lower (8.1 ± 4.5) compared to the hydroxyurea naïve Accra cohort (p=<0.0001). Further studies of the Accra cohort revealed significant correlations between HO-1 and multiple markers of vascular inflammation; sICAM-1(r=0.2794, p=0.03, n=60), sE-selectin (r= 0.4209, p=0.0017, n=58) and sP-selectin (r=0.3855, p=0.0028, n=58). The number of the (GT)n dinucleotide in the HO-1 promoter ranged 17 to 45; the distribution was trimodal with peaks at 23, 30 and 41 repeats. The overwhelming majority of patients had medium and large size alleles that are generally hypo-response to induction. Plasma HO-1 level correlated with the length of the (GT)n dinucleotide repeat (p=0.003, n=80). In a multivariable regression model, WBC, sICAM-1, sE-selectin and sP-selectin accounted for 13.4% of the total variance of plasma HO-1 level, and the (GT)n polymorphism accounted for 9.8%. In conclusion, the concentration of plasma HO-1 is generally raised among SCD patients at steady-state. However, a large proportion of patients have a relatively modest level that is probably inadequate to counter the severity of inflammation typical of SCD, due in part to a hypo-responsive HO-1 promoter. Therapeutic strategies that complement induction of the endogenous HO-1 gene may be critical to ameliorate inflammation in SCD. Disclosures:No relevant conflicts of interest to declare.

Increased MicroRNA-146a Levels in Plasma of Patients with Newly Diagnosed Type 2 Diabetes Mellitus

BackgroundMicroRNAs (miRNAs), a class of small non-coding RNAs, are thought to serve as crucial regulators of gene expression. Dysregulated expression of miRNAs has been described in various diseases and may contribute to related pathologic processes. Our aim was to examine circulating miRNA-146a levels in newly diagnosed type 2 diabetes mellitus (new-T2DM) patients from a Chinese Han population.Methodology/Principal FindingsCirculating miRNA-146a was extracted from plasma samples of 90 new-T2DM patients and 90 age- and sex-matched controls. Quantitative PCR assessment revealed that circulating miRNA-146a levels were significantly elevated in new-T2DM patients compared with controls. Participants in the highest tertile of circulating miRNA-146a levels showed a notably higher risk for new-T2DM (crude OR 4.333, 95% CI, 1.935 to 9.705, P = 0.001) than persons in the lowest tertile. Controlling for known risk factors and some biochemical indicators did not attenuate the aforementioned association. In addition, receiver operating characteristic (ROC) curves generated for miRNA-146a revealed an area under the curve (AUC) of 0.725 (95% CI, 0.651 to 0.799, P < 0.001). Moreover, higher circulating miRNA-146a levels were significantly associated with higher plasma heme oxygenase-1 (HO-1) concentrations (β coefficient = 0.131, P < 0.001) and lower HOMA-beta (β coefficient = -0.153, P = 0.015).Conclusions/SignificanceWe found that circulating miRNA-146a levels were significantly elevated in new-T2DM patients compared with healthy controls. Whether expression of circulating miRNA-146a holds predictive value for T2DM warrants further investigations.

Plasma heme oxygenase-1 level is associated with reduction in extracellular matrix expansion in peri infarct region post acute myocardial infarction

Plasma heme oxygenase-1 level is associated with reduction in extracellular matrix expansion in peri infarct region post acute myocardial infarction

Plasma Heme Oxygenase-1 Levels Distinguish Latent or Successfully Treated Human Tuberculosis from Active Disease

BackgroundTuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB.MethodsCross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India.ResultsSystemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-γ and IL-17 and diminished levels of tumor necrosis factor (TNF)-α.ConclusionThese findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins.

Plasma and Urinary Heme Oxygenase-1 in AKI

AKI induces upregulation of heme oxygenase 1 (HO-1), which exerts cytoprotective effects and modulates the renal response to injury, suggesting that a biomarker of intrarenal HO-1 activity may be useful. Because HO-1 largely localizes to the endoplasmic reticulum and has no known secretory pathway, it is unclear whether plasma or urinary levels of HO-1 reflect intrarenal HO-1 expression. We measured plasma and urinary levels of HO-1 by ELISA during the induction and/or maintenance phases of four mouse models of AKI: ischemia/reperfusion, glycerol-induced rhabdomyolysis, cisplatin nephrotoxicity, and bilateral ureteral obstruction. In addition, we measured levels of HO-1 mRNA and protein in the renal cortex. Each AKI model increased renal HO-1 gene expression, which corresponded with release of HO-1 into plasma and urine by 4 hours. Over time, the magnitudes of plasma and urinary HO-1 paralleled renal cortical gene expression. AKI and the associated uremia did not seem to affect extrarenal HO-1 gene activity assessed in the liver, lung, and spleen. In iron-challenged, cultured proximal tubule cells, we observed a positive correlation between HO-1 mRNA level and HO-1 release. In humans, 10 patients with AKI demonstrated markedly higher levels of plasma and urine HO-1 levels than 10 critically ill patients without AKI or 20 patients with CKD or ESRD. In summary, these data suggest that plasma and urinary HO-1 levels may serve as biomarkers of AKI and intrarenal HO-1 gene activity.

Plasma Heme Oxygenase-1 Concentration in Relation to Impaired Glucose Regulation in a Non-Diabetic Chinese Population

BackgroundOur previous study has recently shown that plasma heme oxygenase-1 (HO-1), a stress-responsive protein, is elevated in individuals with type 2 diabetes. The current study aimed to examine the association between plasma HO-1 concentration and impaired glucose regulation (IGR) in non-diabetic individuals.MethodsWe conducted a case-control study including a total of 865 subjects (262 IGR individuals and 603 healthy controls) in a Chinese population. Basic characteristics were collected by questionnaire and standardized anthropometric measurements. Plasma HO-1 concentration was determined by ELISA.ResultsPlasma HO-1 concentration was significantly increased in IGR individuals compared with healthy controls (1.34 (0.81–2.29) ng/ml vs 0.98 (0.56–1.55) ng/ml, P<0.001). After adjustment for age, sex, and BMI, the ORs for IGR in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 3.42 (95% CI 2.11–5.54; P for trend <0.001). The trend remained significant even after additional adjustment for smoking, alcohol drinking, hypertension, family history of diabetes, lipid profiles and C-reactive protein. In the receiver-operating characteristic curve analysis, addition of plasma HO-1 concentration to a model with known risk factors yielded significantly improved discriminative value for IGR (area under the curves 0.75 (95% CI 0.71–0.78) vs. 0.72 (95% CI 0.69–0.76); P for difference = 0.026).ConclusionsElevated plasma HO-1 concentration is significantly associated with increased ORs for IGR. However, its clinical utility should be validated in further studies, especially in prospective cohort studies.

Plasma Hemoxygenase-1 and Cardiac Enlargement in Chronic Heart Failure Patients

Introduction: Heme oxygenase-1 (HO-1) is a stress protein that is involved in protection of cardiac diaseases from diffrent noxious stimuli. Objective: We investigated whether plasma HO-1 is changed in cronic heart failure (CHF) patients and whether plasma HO-1measurements provide a peripheral biomarker of the disease. Methods: Plasma HO-1, were measured in 24 normal controls (NEC) and in 53 consecitive patients with CHF admitted to the Clinic of Cardiology over the period May 2010 - January, 2011. Systolic dysfunction was defined at left ventricle ejection fraction (LVEF) < 40%. Standardised protocol was used for colecting information on the investigated variables of interest. Plasma HO-1 and Brain natriuretic peptide (BNP) were measured with immunoassays. Depending on the distribution variables are reported with mean and median. Аssociations of the variables with HO-1 were investigated with linear regression analyses. Results: Plasma HO-1 concentrations (ng/ml) were significantly lower in CHF patients (median 2.58, range 0.5-7.3) compared with NEC (median 5.2 range 1.2-12.2) (p < 0.01). Circulating BNP levels were not significantly correlated with plasma HO-1 levels. There was a significant negative correlation between HO1 and serum total bilirubin (p<0.05). A negative weak correlations were also observed with functional class (p<0.05) and atrial fibrillation (p<0.05). Plasma levels of HO-1 showed a significant considerable positive correlation with left ventricle (LV) dimensions values. Independent predictive effects on HO-1 levels in multiple regression analysis (F=8.2, p<0.01) were explored for the values of the LV end-diastolic volume and artrial fibrillation. Conclusion: Plasma HO-1 are decreased in patients with CHF. Levels of HO-1 are independently correlated to the degree of cardiac enlargement. Further studies are needed on the concrete mechanisms of the deranged HO-1 regulation in CHF patients.

Heme Oxygenase 1 Polymorphisms and Plasma Concentrations in Critically Ill Patients

Heme oxygenase 1 (HO-1) is a cytoprotective enzyme upregulated by various critical illness-related stress stimuli. We investigated the association of HO-1 gene polymorphisms and plasma concentrations with the outcome of critically ill patients in a prospective cohort study of 231 critically ill patients admitted to tertiary care medical and medical-surgical intensive care units. Blood samples were collected on days 1, 2, and 3 to 4 in the intensive care unit. The HO-1 plasma concentration was measured in serial samples, and HO-1 single nucleotide polymorphisms, -413A/T and +99G/C, and HO-1 promoter GTn repeat length polymorphism were determined. The +99C and long GTn alleles were in perfect linkage disequilibrium, and the -413T/GT(L)/+99C haplotype had significant independent effect on first-day HO-1 plasma concentrations in linear regression analysis (P = 0.03) and associated with lower HO-1 plasma levels. Furthermore, -413T/GT(L)/+99C haplotype associated with a lower frequency of multiple-organ dysfunction compared with other haplotypes (P = 0.017). The HO-1 plasma concentrations of study patients were significantly higher than the values of healthy controls at all time points (P < 0.001), and the first-day plasma HO-1 levels were independently associated with the Sequential Organ Failure Assessment score (P = 0.001). In conclusion, the HO-1 -413T/GT(L)/+99C haplotype is associated with HO-1 plasma levels and the frequency of multiple-organ dysfunction in critically ill patients. The HO-1 plasma concentrations are significantly increased among critically ill patients and associated with the degree of organ dysfunction.

Plasma Heme Oxygenase-1 Concentration Is Elevated in Individuals with Type 2 Diabetes Mellitus

BackgroundCirculating concentrations of heme oxygenase-1 (HO-1) have been recently reported to be elevated in several chronic disorders. However, no study has ever examined the association between circulating HO-1 concentrations and type 2 diabetes mellitus (T2DM).Methods and Findings581 cases with newly-diagnosed T2DM (New-T2DM) and 611 comparison controls were recruited in this two-phase case-control study, comprising 420 cases and 429 controls collected in the first phase study and 161 cases and 182 controls in the second phase replication study. Analyses, using both separated data and combined data from the two-phase studies, show that plasma HO-1 concentrations were significantly increased in New-T2DM cases compared to controls (P<0.001). Plasma HO-1 concentrations were significantly correlated with plasma glucose concentrations, HOMA-beta and HOMA-IR (P<0.001). After adjustment for age, sex, BMI and family history of diabetes, the ORs for New-T2DM in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 8.23 (95% CI 5.55–12.21; P for trend <0.001). The trend remained significant after additional adjustment for fasting plasma glucose/insulin, HOMA-beta/HOMA-IR, TC/TG, smoking, drinking and history of hypertension, and even in further stratification analysis by age, sex, BMI, smoking, drinking and history of hypertension.ConclusionsElevated plasma HO-1 concentrations are associated with higher ORs for New-T2DM, which add more knowledge regarding the important role of oxidative stress in T2DM. More consequent studies were warranted to confirm the clinical utility of plasma HO-1, especially in diagnosis and prognosis of T2DM and its complications.

Heme Oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome

Heme oxygenase-1 (HO-1) acts in cytoprotection against acute lung injury. The polymorphic (GT)n repeat in the HO-1 gene (HMOX1) promoter regulates HMOX1 expression. We investigated the associations of HMOX1 polymorphisms with acute respiratory distress syndrome (ARDS) risk and plasma HO-1 levels. Unmatched, nested case-control study. Academic medical center. Consecutive patients with ARDS risk factors upon ICU admission were prospectively enrolled. Cases were 437 Caucasians who developed ARDS and controls were 1,014 Caucasians who did not. We genotyped the (GT)n polymorphism and three tagging single nucleotide polymorphisms (tSNPs) in 1,451 patients, and measured the plasma HO-1 levels in 106 ARDS patients. We clustered the (GT)n repeats into: S-allele (<24 repeats), M-allele (24-30 repeats) and L-allele (> or = 31 repeats). We found that longer (GT)n repeats were associated with reduced ARDS risk (Ptrend = 0.004 for both alleles and genotypes), but no individual tSNP was associated with ARDS risk. HMOX1 haplotypes were significantly associated with ARDS risk (global test, P = 0.016), and the haplotype S-TAG was associated with increased ARDS risk (OR, 1.75; 95% CI, 1.15-2.68; P = 0.010). Intermediate-phenotype analysis showed longer (GT)n repeats were associated with higher plasma HO-1 levels (Ptrend = 0.019 for alleles and 0.027 for genotypes). Longer (GT)n repeats in the HMOX1 promoter are associated with higher plasma HO-1 levels and reduced ARDS risk. The common haplotype S-TAG is associated with increased ARDS risk. Our results suggest that HMOX1 variation may modulate ARDS risk through the promoter microsatellite polymorphism.

Biomarker Potential of Heme Oxygenase-1 in Alzheimer‘s Disease and Mild Cognitive Impairment

The advent of an accessible chemical biological marker that differentiates early, sporadic Alzheimer's disease (AD) from normal aging and other dementing illnesses, and identifies individuals with mild cognitive impairment who are destined to deteriorate to Alzheimer's dementia, would represent a major achievement in the evaluation and management of this common neurodegenerative disorder. Although several candidate biomarkers of sporadic AD have been identified and commercialized, none currently fulfill the criteria for an ideal test. In this article, we review evidence implicating blood heme oxygenase-1 mRNA/protein levels and a recently identified plasma heme oxygenase-1 suppressor factor as potential biomarkers of AD and mild cognitive impairment.

Steady plasma concentration of unfractionated heparin reduces infarct volume and prevents inflammatory damage after transient focal cerebral ischemia in the rat.

Unfractionated heparin (UH) decreases the extent of infarction after transient focal brain ischemia in the rat and abridges neuroinflammatory damage in patients with acute stroke. This study was aimed at assessing whether controlled and steady heparinemia in plasma can reduce infarct volume and exert neuroprotective effects after ischemia. Infarct volume was measured at 24 and 7 days following a 1-hr intraluminal middle cerebral artery (MCA) occlusion in rats treated with UH or with vehicle. After testing several UH administration protocols, we choose to give a bolus of 200 U/kg, which was started 3 hr after the occlusion, followed by a 24-hr intraperitoneal perfusion of 70 U/kg/hr, which maintained a 24-hr steady plasma heparinemia (0.3-0.6 U/ml) and caused no CNS or systemic bleeding. In addition, plasma IL-10 concentration was measured by ELISA, endothelial VCAM-1 expression was evaluated by i.v. injection of a (125)I-labeled monoclonal antibody against VCAM-1, and brain hemeoxygenase-1 (HO-1) expression was determined by Western blot. UH-treated rats showed smaller infarctions than rats treated with vehicle, as well as higher IL-10 plasma levels and HO-1 brain expression and lower endothelial VCAM-1 induction. The study shows that a stable plasma concentration of UH given at nonhemorrhagic doses reduces infarct volume after ischemia-reperfusion in the rat. It also shows that UH prevented the induction of cell adhesion molecules in the cerebral vasculature and increased the expression of molecules with antiinflammatory and prosurvival properties. These findings support further testing of the clinical value of parenteral, adjusted, high-dose UH in patients with acute stroke.