Demet Tekin

Hypoxia inducible factor 1 (HIF-1) and cardioprotection

AbstractSince its discovery in early 1990s, hypoxia inducible factor 1 (HIF-1) has been increasingly recognized for its key role in transcriptional control of more than a hundred genes that regulate a wide-spectrum of cellular functional events, including angiogenesis, vasomotor control, glucose and energy metabolism, erythropoiesis, iron homeostasis, pH regulation, cell proliferation and viability. Evidence accumulated during the past 7 years suggests a critical role for HIF-1α in mediating cardioprotection. The purpose of our present article is to provide an updated overview on this important regulator of gene expression in the cellular stress-responsive and adaptive process. We have particularly emphasized the involvement of HIF-1 in the induction of cardioprotective molecules, such as inducible nitric oxide synthase (iNOS), hemeoxygenase 1 (HO-1), and erythropoietin (EPO), which in turn alleviate myocardial damages caused by harmful events such as ischemia-reperfusion injury. Despite these advances, further in-depth studies are needed to elucidate the possible coordination or interaction between HIF-1α and other key transcription factors in regulating protein expression that leads to cardioprotection.

Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent pathway in mice.

We recently demonstrated that monophosphoryl lipid A (MLA)-induced delayed cardioprotection is mediated by inducible nitric oxide synthase (iNOS) in mice. In the present study, we determined whether RC-552, a novel synthetic glycolipid related in chemical structure to MLA, could afford similar protection. Adult mice were pretreated with vehicle or RC-552 (350 μg/kg ip, n = 7 mice/group) 24 h before global ischemia and reperfusion in a Langendorff isolated, perfused heart model. A group of RC-552-treated mice received S-methylisothiourea (SMT), a selective inhibitor of iNOS (3 mg/kg ip), 30 min before heart perfusion. Myocardial infarct size was significantly reduced from 19.2 ± 2.0% in vehicle to 8.2 ± 2.9% in RC-552 group ( P < 0.05). Treatment with SMT abolished RC-552-induced reduction in infarct size (20.0 ± 3.9%). In addition, RC-552 failed to reduce infarct size in isolated hearts from iNOS knockout mice (27.1 ± 2.8%) compared with that in hearts from control knockout mice without drug treatment (22.9 ± 5.4%). Acute buffer perfusion with RC-552 (0.1, 1.0, or 2.5 μg/ml) for 8 min immediately before ischemia-reperfusion did not reduce infarct size significantly. We concluded that RC-552 induces delayed cardioprotection via an iNOS-dependent pathway.

Whole body hyperthermia and preconditioning of the heart: basic concepts, complexity, and potential mechanisms

Whole body hyperthermia (WBH) is a distinctive pathophysiological condition with significant impact on tissue metabolism and organ functions. WBH has been investigated as a promising adjunct therapy to the conventional chemo- or radiotherapy for treating certain types of cancer. Numerous studies have shown that WBH is associated with induction of heat shock proteins (HSPs), which in turn modulate cellular survival or death. A brief period of WBH (40-42°C; 15-20min) can induce delayed protection against lethal endotoxemia as well as various forms of injury in brain, heart, liver, lungs, small intestine, and skeletal muscle. This review article focuses on discussing the WBH-induced myocardial protection against ischemia/reperfusion injury. Most recently, possible involvement of protein kinase C, mitogen-activated protein kinases, nitric oxide, ATP-sensitive potassium channels, and neural peptides in the signal transduction pathways has been demonstrated. On the other hand, whether HSPs or antioxidant enzymes are the primary end-effector of the cardioprotection continues to be a matter of ongoing debates. It has also been recognized that the complex nature of WBH may be the responsible factor for the discordant results among various studies, especially across different animal species or strains, in terms of the time course and potency of WBH-induced cardioprotection. Nevertheless, a better understanding of the WBH-elicited myocardial ischemic resistance may have a wide spectrum of clinical implications as well as insightful inputs into the hyperthermic biology.Whole body hyperthermia (WBH) is a distinctive pathophysiological condition with significant impact on tissue metabolism and organ functions. WBH has been investigated as a promising adjunct therapy to the conventional chemo- or radiotherapy for treating certain types of cancer. Numerous studies have shown that WBH is associated with induction of heat shock proteins (HSPs), which in turn modulate cellular survival or death. A brief period of WBH (40-42 degrees C; 15-20 min) can induce delayed protection against lethal endotoxemia as well as various forms of injury in brain, heart, liver, lungs, small intestine, and skeletal muscle. This review article focuses on discussing the WBH-induced myocardial protection against ischemia/reperfusion injury. Most recently, possible involvement of protein kinase C, mitogen-activated protein kinases, nitric oxide, ATP-sensitive potassium channels, and neural peptides in the signal transduction pathways has been demonstrated. On the other hand, whether HSPs or antioxidant enzymes are the primary end-effector of the cardioprotection continues to be a matter of ongoing debates. It has also been recognized that the complex nature of WBH may be the responsible factor for the discordant results among various studies, especially across different animal species or strains, in terms of the time course and potency of WBH-induced cardioprotection. Nevertheless, a better understanding of the WBH-elicited myocardial ischemic resistance may have a wide spectrum of clinical implications as well as insightful inputs into the hyperthermic biology.

The antioxidative defense in asthma

Asthma is a disease characterized by chronic airway inflammation. Generation of oxygen free radicals by activated inflammatory cells produces many of the pathophysiologic changes associated with asthma and may contribute to its pathogenesis. However, the activities of antioxidant enzymes and their relation with asthma have not been well defined. This study was performed to examine the activities of major intracellular antioxidants in mild asthmatic patients. Twelve asymptomatic mild asthmatic patients who never used any antiasthma medication and 13 age- and sex-matched healthy control subjects were selected. The activities of erythrocyte antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione-peroxidase (GSH-Px) were measured spectrophotometrically. The mean SOD activity of asthmatic patients was found to be significantly lower than that of the controls (p < 0.05). There was no significant difference in CAT and GSH-Px activities between patients and controls (p > 0.05). Although the mechanisms underlying the association between asthma and antioxidant system are unclear, according to our findings, decreased antioxidant protection may contribute to the pathogenesis of mild asthma.

Possible effects of antioxidant status on increased platelet aggregation in childhood iron-deficiency anemia

Background : Alterations in platelet function and antioxidant status in children with iron‐deficiency anemia (IDA) have been reported previously. The present study was performed to better understand possible interactions between these two systems.

Influence of knee osteoarthritis on exercise capacity and quality of life in obese adults.

Objective: The objective was to determine whether knee osteoarthritis (OA) reduces exercise ambulatory capacity and impairs quality of life (QOL) in obese individuals.

The effects of acute and intermittent hypoxia on the expressions of HIF-1α and VEGF in the left and right ventricles of the rabbit heart.

OBJECTIVE Hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) are involved in signaling mechanisms of cellular responses to hypoxia. These factors have been investigated in tissue samples by simulating different altitudes by changing the percentage of oxygen. We aimed first to evaluate the effect of normobaric, systemic hypoxia (11% O2) on HIF-1α and VEGF mRNA levels in the heart muscle; secondly, to compare the levels of HIF-1α and VEGF mRNA in the left and right ventricle muscles. METHODS In this experimental study, 33 New Zealand male rabbits were assigned to control, acute hypoxia (4 hours) and intermittent hypoxia (4 hours/day for 14 days) groups (n=11/group). Total RNA was isolated from right and left ventricles of the heart. The expressions of HIF-1α and VEGF mRNAs were investigated by using Reverse Transcription Polymerase Chain Reaction (RT-PCR) method. The obtained data were compared by using ANOVA and paired t-test. RESULTS The results indicated that left ventricle VEGF mRNA expressions in both acute and intermittent hypoxia groups (1.08 ± 0.15 and 1.03 ± 0.19, respectively) were higher than that in the control group (0.88 ± 0.15) (p=0.03). Hypoxia treatments did not significantly alter HIF-1α mRNA in both ventricles (p=0.60 and p=0.51 for left and right ventricles, respectively). CONCLUSION Since systemic hypoxia results in induction of VEGF mRNA up-regulation only in left ventricle, it could be related to its higher metabolic activity and oxygen utilization. Hypoxia induced changes in the expression of HIF-1α mRNA may not be the only determining factor for HIF-1/VEGF pathway induction or the observed VEGF induction could be through other hypoxia sensitive pathways.

Genetic deletion of fas receptors or Fas ligands does not reduce infarct size after acute global ischemia-reperfusion in isolated mouse heart.

Apoptosis has been shown in cardiac cells under divergent physiological and pathological conditions. However, there has been an ongoing debate upon the relative contribution of cardiomyocyte apoptosis to the myocardial infarct size after ischemia-reperfusion (I-R) injury. We tested the hypothesis that blocking the death receptor pathway of apoptosis through genetic deletion of Fas receptors or Fas ligands would reduce myocardial infarct size caused by acute I-R injury. The hearts isolated from Fas receptor or Fas ligand knockout (KO) mice as well as the C57BL/6J wild-type control mice (N=6–8 per group) were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. Our results show that the infarct size, determined with triphenyltetrazolium chloride staining, was not significantly different between the three groups (i.e., 30.2±3.9% for wild-type controls, 30.0±2.1% for Fas ligand KOs, and 23.8±3.6% for Fas receptor KOs; mean±SEM, p>0.05). Postischemic leakage of lactate dehydrogenase, another marker of necrotic cellular injury, also was not significantly different between these groups (p>0.05). In addition, postischemic ventricular contractile function as well as coronary flow were similar for all the experimental groups (p>0.05). In conclusion, contrary to our original hypothesis, the present study in the gene KO mice suggests that the Fas ligand- and Fas receptor-mediated death receptor pathway of apoptosis is not the primary determinant of myocardial infarct size and ventricular dysfunction caused by acute global I-R injury in the isolated perfused mouse heart.