Naglaa K. Idriss

Hemoxygenase-1 in Cardiovascular Disease

Hemoxygenase (HO)-1 is an inducible isoform of the first and rate-controlling enzyme of the degradation of heme into iron, carbon monoxide, and biliverdin, the latter being subsequently converted into bilirubin. Several positive biological effects exerted by this enzyme have gained attention, as anti-inflammatory, antiapoptotic, angiogenic, and cytoprotective functions are attributable to carbon monoxide and/or bilirubin. Thus, the physiological induction of HO-1 may be an adaptive and beneficial response to several possibly noxious stimuli, including heme itself, suggesting a potentially autoprotective and autodefensive role in several pathophysiological states including acute coronary syndromes and stroke. This review article provides a comprehensive overview of the biochemistry, physiology, and pathophysiology of HO-1 in relation to cardiovascular disease (CVD). Furthermore, we present some of the emerging evidence in support of the view that the induction of the HO-1 gene may be a new opportunity to target the pathophysiology of CVD, with therapeutic implications for management.

The effect of melatonin on plasma markers of inflammation and on expression of nuclear factor-kappa beta in acetic acid-induced colitis in the rat.

Background and AimsMelatonin may be involved in gastrointestinal tract physiology and could affect inflammation-related gastrointestinal disorders. Rat models of ulcerative colitis imply melatonin is beneficial. To determine potential pathophysiological mechanisms, we assessed colonic nuclear factor-kappa beta expression and measured serum levels of pentraxin-3, lipid peroxides, and total thiols in an acetic acid model of this disease.Materials and MethodsThirty rats were divided into five groups: a control group, an acetic acid-induced colitis group, a group treated with melatonin before colitis induction, a group treated short-term after colitis induction, and a group treated long-term after colitis induction. After four weeks, blood samples were taken for measurement of pentraxin-3, lipid peroxide, and total thiols. Sections of the colon were taken for histopathological examination and immunohistochemical detection of nuclear factor-kappa beta expression.ResultsMelatonin administration reduced nuclear factor-kappa beta immunohistochemical expression, reduced serum levels of lipid peroxide and pentraxin-3, and maintained serum levels of total thiols. However, in long-term treatment the protective effect of melatonin was not as marked.ConclusionMelatonin is effective in prevention and short-term treatment of the inflammatory process in acetic-acid induced colitis whereas the benefit of long-term treatment is unclear. Benefit may be linked to protection mechanisms against inflammatory processes by inhibiting the nuclear factor-kappa beta and conserving endogenous antioxidant reserves of total thiols, thus reducing the level of colonic damage possibly caused by lipid peroxides.

Plasma haemoxygenase-1 in coronary artery disease. A comparison with angiogenin, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor.

It was the aim of this study to determine plasma haemoxygenase-1 (HO-1) across the spectrum of health, angina but normal coronary arteries (NCA), stable coronary artery disease (CAD), and acute coronary syndromes (ACS), and relationships with angiogenin, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1, and vascular endothelial growth factor. Plasma markers were measured (ELISA) in peripheral venous citrated plasma from 50 healthy subjects, 30 with NCA, 70 with stable CAD and 24 with an ACS, and from patients aortic root, coronary ostium, coronary sinus and femoral artery. Human umbilical vein endothelial cells (HUVECs) were cultured with or without tumour necrosis factor (TNF), and platelets were probed. HO-1 was raised in stable CAD (p<0.05) and increased further in ACS (p<0.01) compared to healthy controls and NCA. HO-1 correlated only with MMP-9, and then only in the healthy controls. There were no major differences from cardiac or peripheral sites. HO-1 was present in HUVECs and 24-hour HUVEC supernatants but release was abolished by TNF. Platelets had no HO-1. In conclusion, HO-1 is raised in stable CAD and ACS and may arise from the endothelium but not the platelet. This may have implications for our understanding of the pathophysiology of CAD and its acute presentation as ACS.

Effects of propofol and isoflurane on haemodynamics and the inflammatory response in cardiopulmonary bypass surgery.

ABSTRACT Cardiopulmonary bypass (CPB) causes reperfusion injury that when most severe is clinically manifested as a systemic inflammatory response syndrome. The anaesthetic propofol may have anti-inflammatory properties that may reduce such a response. We hypothesised differing effects of propofol and isoflurane on inflammatory markers in patients having CBP. Forty patients undergoing elective CPB were randomised to receive either propofol or isoflurane for maintenance of anaesthesia. CRP IL-6, IL-8, HIF-1α (ELISA), CD11 and CD18 expression (flow cytometry), and haemoxygenase (HO-1) promoter polymorphisms (PCR/electrophoresis) were measured before anaesthetic induction, 4 hours post-CPB, and 24 hours later. There were no differences in the 4 hours changes in CRP IL-6, IL-8 or CD18 between the two groups, but those in the propofol group had higher HIF-1α (P=0.016) and lower CD11 expression (P=0.026). After 24 hours, compared to the isoflurane group, the propofol group had significantly lower levels of CRP (P<0.001), IL-6 (P<0.001) and IL-8 (P<0.001), with higher levels CD11 (P=0.009) and CD18 (P=0.002) expression. After 24 hours, patients on propofol had increased expression of shorter HO-1 GT(n) repeats than patients on isoflurane (P=0.001). Use of propofol in CPB is associated with a less adverse inflammatory profile than is isofluorane, and an increased up-regulation of HO-1. This supports the hypothesis that propofol has anti-inflammatory activity.

Plasma levels of neutrophil gelatinase-associated lipocalin in children with heart failure.

Introduction: Data about plasma levels of neutrophil gelatinase-associated lipocalin (NGAL) in children with heart failure (HF) are very limited. NGAL is used widely as a biomarker for the diagnosis of renal injury in numerous clinical studies. The aim of this study is to investigate the plasma NGAL in children with HF caused by idiopathic dilated cardiomyopathy (IDCM) and its relation to the severity of HF. Material and methods: In a case-control study, 30 nondiabetic children, aged –16 years (all have IDCM) recruited from the pediatric department of our institute together with 30 healthy children were prospectively enrolled in this study. Patients underwent a detailed history taking, clinical examination, New York Heart Association (NYHA) class assessment and echocardiographic evaluation. Plasma levels of NGAL were measured by enzyme-linked immunosorbent assay. Results: Plasma levels of NGAL were significantly higher in children with HF compared with healthy controls (mean: 290.97 versus 144.33, p < 0.0001). The relationship between NGAL and the severity of HF was investigated. However, we did not find any statistically significant relationship between plasma NGAL levels and indices of myocardial function. Conclusions: NGAL levels were significantly increased in children with HF caused by IDCM. However, there was no significant relationship between plasma NGAL levels and indices of myocardial function. Future multicenter clinical studies in a large population addressing the natural course of NGAL in HF and its potential as a treatment target are needed in the near future.

Circulating Endothelial Cells and Platelet Microparticles in Mitral Valve Disease With and Without Atrial Fibrillation

Hypercoagulability in mitral valve disease (MVD), a cause of atrial fibrillation (AF) and stroke, is potentially due to endothelial damage/dysfunction (marked by circulating endothelial cells [CECs]), platelet activation (soluble P-selectin [sPsel], platelet microparticles [PMPs], and soluble CD40 [sCD40]), and oxidized low-density lipoprotein (oxLDL) cholesterol. We measured these variables in 24 patients with MVD as well as in 21 with MVD + AF and compared them with 20 healthy controls (HCs). The CECs and PMPs were measured by flow cytometry; sPsel, oxLDL, and CD40 by enzyme-linked immunosorbent assay. Compared with HCs, sPsel and PMPs were equally higher in MVD and MVD + AF; sCD40 and oxLDL were higher in MVD + AF than in HCs and MVD; and CECs were higher in MVD than in the HCs, with further increases in MVD + AF (all P < .001). We conclude that excess platelet activation is present in MVD regardless of AF, and that increased endothelial damage in MVD is greater when compounded by AF.

Implication of tumor necrosis factor alpha receptor 1 and hexosaminidase: relationship to pathogenesis of liver diseases

Liver disease is the main cause of morbidity and mortality worldwide. The spectrum of the disease ranged from fatty liver to hepatic inflammation, necrosis, progressive fibrosis, and hepatocellular carcinoma. We evaluated the serum levels of soluble tumor necrosis factor alpha receptor 1, total B-hexosaminidase and its isoenzymes Hex A and B activities, and nitric oxide in patients with liver diseases and their association with aminotransferase level. Seventy patients and 12 healthy subjects were recruited. Patients were divided into three groups: chronic hepatitis group (20 patients), liver cirrhosis group (30 patients), and malignant liver group (20 patients). Serum levels of soluble tumor necrosis factor alpha receptor 1, total B-hexosaminidase and its isoenzymes Hex A and B activities, and nitric oxide were measured. Serum levels of soluble tumor necrosis factor alpha receptor 1, total B-hexosaminidase activity, and nitric oxide were significantly higher in the liver disease patients. Serum levels of isoenzymes Hex A and B were significantly higher in malignant liver patients. Total B-hexosaminidase and its isoenzyme Hex A activity levels were significantly higher in positive HBsAg and positive anti-HCV patients. Serum levels of soluble tumor necrosis factor alpha receptor 1 were positively correlated with aminotransferase level. Taken together, these findings suggested that these biochemical indices might reflect ongoing disease activity and played an important role in the pathophysiology of liver diseases.

Treatment Efficiency of Different Routes of Bone Marrow-Derived Mesenchymal Stem Cell Injection in Rat Liver Fibrosis Model

Background/Aims: The most appropriate route for bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation in the management of liver fibrosis remains controversial. This study investigated the therapeutic efficacy of intravenous and intrasplenic BM-MSC transplantation on carbon tetrachloride (CCl4)-induced rat liver fibrosis. Methods: Fifty rats were divided into 5 groups (n = 10 rats per group): healthy control group, CCl4 group, CCl4/ recovery group, CCl4/BM-MSC intravenous group, and CCl4/BM-MSC intrasplenic group. BM-MSCs were isolated, labeled with green fluorescent protein (GFP), and injected into fibrotic rats either intravenously or intrasplenically. Gene expression of interleukins (IL-1β and IL-6), interferon (INF)-γ, hepatic growth factor, and the hepatocyte-specific marker cytokeratin 18 was estimated by quantitative real-time reverse transcription-polymerase chain reaction. Vascular endothelial growth factor and connective tissue growth factor was detected by western blot analysis and enzyme-linked immunosorbent assay, respectively. At 2 weeks after intravenous and intrasplenic BM-MSC injections, GFP-positive cells were detected in liver tissue. Results: Both routes achieved a similar enhancement of liver function, which was confirmed by histopathological examination. The intravenous route was more effective than the intrasplenic route in reducing gene expression levels of IL-1β, IL-6, and INF-γ. However, fibrotic changes were still observed in the recovery group. Conclusion: Intravenous BM-MSC injection was an efficient and appropriate route for BM-MSC transplantation for the management of liver fibrosis.

The Relationship between Retinol-Binding Protein-4 and Cardiometabolic Risk Factors in Obese Patients with Type 2 Diabetes Mellitus

Background: Retinol-binding protein-4 (RBP4) is an adipocyte-secreted hormone considered to link obesity with cardiovascular complications. The oxidative stress has been implicated in the pathophysiology of obesity. We evaluated serum RBP4 and plasma total thiols (TT) in generalized obesity (GO) and abdominal obesity (AO) in relationship to classical cardiovascular risk factors. Glycated haemoglobin (HbA1c%), C-reactive protein (CRP) and lipid profile were also evaluated. Patients and Methods: Sixty obese patients were recruited [30 abdominally obese (AO) patients, (15 male and 15 female, mean (SD), 49.5 (5.5) years) were measured by waist circumference (WC > 102 cm for men or > 88 cm for women) and waist/hip ratio (WC divided by that of the hips of > 0.9 for men and > 0.85 for women)] and [30 generalized obese (GO) patients (22 male and 8 female; mean (SD); 42.5 (8) years) were measured by body mass index (BMI). [BMI ≥ 30.0-34.9 kg/m2, with normal WC] compared to 20 healthy subjects (14 males and 6 females; mean age (SD); 36.60 (5.97) years). Results: AO had significantly higher circulating RBP4 levels in comparison to GO (p< 0.05). Total thiols levels were significantly lower in AO compared to GO patients (p< 0.05). CRP significantly elevated in AO compared to GO patients (p<0.05). Total serum cholesterol, triglycerides and Hb1Ac% increased with BMI, WC and waist/hip ratio (WHR). Conclusion: The study reveals that RBP4 is autonomously related to visceral fat accumulations and cardiovascular diseases. The study also reveals the beneficial effect of TT against obesity and cardiovascular disease and the potential clinical applicability of RBP4 and total thiols in cardiovascular diseases.

Relationship of angiogenin to pathophysiology of diseases

Angiogenin is a powerful stimulator of new blood vessel formation. It is a member of pancreatic ribonuclease (RNase) superfamily. It was originally isolated from conditioned medium of cultured tumor cells. Along with other associated molecules, it has been recognized in a variety of somatic tissues in embryonic stages and adult of vertebrate development. It binds to high-affinity endothelial cell surface receptors and, with lower affinity, to extracellular matrix. This suggests that angiogenin and related molecules are likely to play a vital role in normal physiology, even though the biological significance of angiogenin is uncertain due to weak catalytic activity of the protein. It has a significant critical role in angiogenesis. Angiogenin transported to the nucleus after being endocytosed by endothelial cell, where it was built up in the nucleolus and is a normal constituent of the circulation, rarely undergoes proliferation and promotes neovascularization. In blood angiogenin, levels increase in some physiological and pathological conditions, which may be of a prognostic significance. It also plays an important role in a number of nonmalignant vasculo-proliferative pathological conditions such as inflammatory bowel disease, proliferative diabetic retinopathy, cardiovascular diseases, and rheumatoid arthritis and in malignant diseases such as colorectal, gastric, pancreatic, melanoma, and urothelial cancer lesions. This review article aims to give an overview of the biochemical structure, receptor translocation, physiology, and types of angiogenin, in addition to its main role in pathological states and ultimately its effect as a beneficial therapeutic approach.