Mitochondrial and Cellular Heme-Dependent Proteins as Targets for the Bioactive Function of the Heme Oxygenase/Carbon Monoxide System
ABSTRACT The toxic effect of high concentrations of CO gas in living organisms is coherently typified at biochemical levels by the high affinity of CO for hemoglobin and cytochromes, heme-dependent proteins that are indispensable for oxygen transport and mitochondrial respiration. However, the basal production of CO during heme degradation and the ability of heme oxygenase-1 (HO-1) to increase CO availability pose the question of how this gaseous molecule interacts with metal centers within the intracellular milieu to serve as one of the most unconventional signaling mediators. Emerging evidence indicates that the diverse and multifaceted beneficial effects exerted by "low concentrations" of CO cannot be explained solely by the activation of classic prototypic targets (i.e., guanylate cyclase/potassium channels) but entails the dynamic and concerted activation/inhibition of a group of CO-responsive proteins. As the complexity of the temporal and spatial action of CO is progressively being appreciated, this review aims to (a) highlight the current knowledge on certain metal-containing proteins that interact directly with CO; (b) analyze the latest notions on their functional role in response to CO; and finally (c) propose a rational view on the mode these CO targets may interrelate with and be regulated by the HO/CO pathway.
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- "Some authors have suggested that Hsp32 might be destructive in these conditions because it breaks down heme into ferrous iron, potentially increasing the risk for Fenton chemistry and iron toxicity (Schipper 2011). Indeed, heme-derived iron and carbon monoxide may both increase the risk for oxidative stress (Desmard et al. 2007; Zhang and Piantadosi 1992). On the other hand, coinduction of apoferritin appears to limit Hsp32 toxicity (Dennery 2000; Ryter and Tyrrell 2000), and many studies have verified that Hsp32 is protective (Calabrese et al. 2009; Jazwa and Cuadrado 2010; Zhang et al. 2013). "
ABSTRACT: Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stress-induced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.Journal of Cell Communication and Signaling 09/2014; 8(4). DOI:10.1007/s12079-014-0243-9
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- "Although Hsp32/HO-1 in testis after hyperthermia or other treatments has been intensely investigated, the molecular mechanisms regarding the anti-apoptotic role of Hsp32/HO-1 are poorly understood. Many of the protective effects of Hsp32/HO-1 induction have been attributed to two of its products, CO (Otterbein et al., 2003a; Maines and Gibbs, 2005; Desmard et al., 2007; Bilban et al., 2008) or bilirubin (Stocker et al., 1987; Clark et al., 2000; Erario et al., 2002). Hsp32/HO-1 has anti-inflammatory, antiapoptotic , and anti-proliferative effects in different systems (Morse and Choi, 2002; Bilban et al., 2008). "
ABSTRACT: Heat shock protein 32 (Hsp32)/ heme oxygenase-1 (HO-1) is believed to represent a key enzyme for the protection of cells against stress. The anti-apoptotic effect of Hsp32/HO-1 has been attributed to its product carbon monoxide (CO) in many types of cells; however, whether the anti-apoptotic mechanism plays a role in Sertoli cells is not yet clear. We hypothesize that Hsp32/HO-1 and CO generated from Hsp32/HO-1 provide survival advantages in Sertoli cells by preventing apoptosis under heat exposure. Therefore, the aim of our investigations was to identify the possible roles of Hsp32/HO-1 in hyperthermia stress Sertoli cells. After treatment of cultured mouse Sertoli cells with hyperthermia or/and Hsp32/HO-1 activator Hemin, we evaluated apoptosis by annexin V-FITC and caspase-3 activation. In addition, we analyzed the Hsp32/HO-1-derived CO contents in cultured media and cyclic guanosine monophosphate (cGMP) production by enzyme-linked immunosorbent assay (ELISA). The results showed that the hyperthermia induced Sertoli cells apoptosis, while preincubation with Hemin suppressed Sertoli cell apoptosis induced by hyperthermia treatment. Hyperthermia or/and Hemin increase Hsp32/HO-1 gene expression and the production of CO which, in turn, stimulates the generation of cGMP. Taken together, our results suggest that Hsp32/HO-1 is a protective factor in heat-stressed Sertoli cells, and that CO generated from Hsp32/HO-1 is involved in the anti-apoptotic pathway.Cell Biology International 01/2014; 38(1). DOI:10.1002/cbin.10177 · 1.64 Impact Factor
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- "Carbon monoxide (CO) is a product of heme oxygenase activity that serves as an anti-inflammatory signaling molecule in mammalian cells ,  by binding, among others, divalent metals of heme-containing proteins such as guanylate cyclase, mitochondrial cytocrome c oxidase and NADPH oxidase , , . CO selectively inhibits the expression of pro-inflammatory cytokines, increasing the anti-inflammatory cytokine IL-10 , ,  and reducing neutrophil migration in septic lungs by suppressing transendothelial migration . "
ABSTRACT: Chronic infections resulting from biofilm formation are difficult to eradicate with current antimicrobial agents and consequently new therapies are needed. This work demonstrates that the carbon monoxide-releasing molecule CORM-2, previously shown to kill planktonic bacteria, also attenuates surface-associated growth of the gram-negative pathogen Pseudomonas aeruginosa by both preventing biofilm maturation and killing bacteria within the established biofilm. CORM-2 treatment has an additive effect when combined with tobramycin, a drug commonly used to treat P. aeruginosa lung infections. CORM-2 inhibited biofilm formation and planktonic growth of the majority of clinical P. aeruginosa isolates tested, for both mucoid and non-mucoid strains. While CORM-2 treatment increased the production of reactive oxygen species by P. aeruginosa biofilms, this increase did not correlate with bacterial death. These data demonstrate that CO-RMs possess potential novel therapeutic properties against a subset of P. aeruginosa biofilm related infections.PLoS ONE 04/2012; 7(4):e35499. DOI:10.1371/journal.pone.0035499 · 3.23 Impact Factor