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• W2109224621 abstract "Editorial FocusOxidative stress in carotid body contributes to enhanced chemoreflex in heart failure: focus on “Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits”Samuel H. H. Chan, and Julie Y. H. ChanSamuel H. H. ChanCenter for Translational Research in Biomedical Sciences, Chang Gung Memorial Hospital–Kaohsiung Medical Center; and , and Julie Y. H. ChanDepartment of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of ChinaPublished Online:01 Feb 2010https://doi.org/10.1152/ajpregu.00792.2009This is the final version - click for previous versionMoreSectionsPDF (39 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat chronic heart failure (CHF) is characterized by exaggeration of sympathetic nerve activity (SNA) that elicits dual effects. By maintaining cardiac output and preserving cardiovascular homeostasis during CHF, sympathoexcitation is initially a beneficial compensatory mechanism. Sustained activation of SNA, however, exacerbates cardiovascular deterioration, leading to cardiac decompensation and progression of CHF (11). The sympathetic hyperactivity observed in CHF is closely related to abnormalities in cardiovascular reflexes. Thus, sympathoinhibitory cardiovascular reflexes, such as the arterial baroreflex, are depressed, and sympathoexcitatory reflexes, including cardiac sympathetic afferent reflex and arterial chemoreflex, are significantly augmented (12, 13). In addition to reports on the increase of sympathetic outflow from the central nervous system, a series of studies from Dr. Harold Schultz's laboratory during the past few years showed that hypersensitivity of peripheral chemoreceptors is also involved in the enhancement of chemoreflex that leads to sympathetic activation in CHF (9).Activation of chemoreceptors in the aortic body and carotid body (CB) initiates the arterial chemoreflex in response to hypoxia. Although controversy still exists on details of the chemoneurotransduction cascade in the CB, the general consensus depicts that the glomus or type I cells, which lie in synaptic apposition with afferent axons, are the initial sites of chemotransduction in the CB. The glomus cell expresses several types of membrane ion channels that influence its excitability. Of these channels, the hypoxia-inactivated outward K+ channels are known to play a key role in the initial depolarization, with subsequent activation of voltage-gated Ca2+ channels, release of neurotransmitters, and increase of sensory discharge in the carotid sinus nerve (4). In CB glomus cells from CHF rabbits, the outward voltage-gated K+ current (Ik) is suppressed and their sensitivity to hypoxic inhibition is enhanced, resulting in discharge of chemoreceptor afferents under normoxic state and an increase in discharge responsiveness to hypoxia (9). The observations that these alterations occur in intact (blood perfused) and isolated CB cells suggest that an intrinsic alteration within the CB, rather than a circulating factor, drives the augmented chemoreceptor afferent sensitivity in the CHF state (10).Contemporary efforts to delineate the molecular mechanism underlying the enhancement of CB chemoreceptor sensitivity in CHF focused on the reactive oxygen species, in particular superoxide anion (O2−), and the enzymes that are involved in the generation or degradation of the reactive oxygen species. In a rabbit model of left ventricular pacing-induced CHF, Li et al. (6) reported that both mRNA and protein expressions of NADPH oxidase components (gp91phox, p40phox, and p47phox) are upregulated, and the NADPH oxidase-derived O2− signaling pathway contributes to the enhanced chemoreceptor sensitivity to hypoxia by suppressing Ik currents in CB glomus cells (9). The causal relationship between oxidative stress and the enhanced CB chemoreceptor activity in CHF is further confirmed by observations that adenovirus-mediated gene transfer to the CB tissue of copper/zinc-superoxide dismutase (CuZn-SOD), the major cytosolic antioxidant enzyme regulating O2− metabolism, effectively reduces the elevated O2− levels and reverses the enhanced CB chemoreceptor hypersensitivity and reflex function during normoxia and isocapnic hypoxia (3). This is accompanied by normalization of the blunted Ik currents in CB glomus cells in CHF rabbit.In addition to the cytosol, Ding et al. (2) reported that the mitochondrion could be another cellular source of O2− in CB chemoreceptors mediating an enhanced chemoreflex in CHF. The authors showed suppressed mitochondrial manganese SOD (MnSOD) expression and elevated mitochondrial O2− levels in CB glomus cells of CHF rabbits. Overexpression of MnSOD by adenovirus gene transfer selectively to the CB increases MnSOD expression and reverses the elevated mitochondrial O2− levels in CB tissue, along with normalization of enhanced chemoreflex response to hypoxia. This is accompanied by a decrease in baseline discharge of chemoreceptor afferents, chemoreceptor hypersensitivity to hypoxia, and reversal of the blunted Ik in CB glomus cells. These results suggest that decreased mitochondrial MnSOD in the CB and elevated mitochondrial O2− levels contributes to the enhanced CB chemoreceptor activity and peripheral chemoreflex function in CHF rabbits.This study is a logical extension of previous work by the same group showing the importance of NADPH oxidase-derived O2− and cytosolic SOD in the augmented chemoreflex function in CHF (1, 3, 5–9). Their findings highlight the significance of mitochondrial O2− and its degradation by MnSOD in the pathophysiology of CB chemoreceptor hypersensitivity and enhanced chemoreflex in CHF. However, with observations that O2− generated from different subcellular compartments contributes almost equally to the enhanced chemoreflex in CHF, several questions emerged that need to be answered. For example, are the downstream signaling cascades mediating the gating of the hypoxia-inactivated outward K+ channels in CB by O2− derived from NADPH oxidase and mitochondrion the same or different? Are these signaling pathways modified under CHF condition? What are the mechanisms that underlie the downregulation of CuZn-SOD and MnSOD expression in CB glomus cells in CHF? Since insertion of a CuZn-SOD (3) or a MnSOD (2) transgene in the CB almost completely reverses the augmented chemoreflex function in the CHF rabbit, is there any interaction between them in regulation of O2− level in CB glomus cells under normal or CHF conditions? Obviously, answers to these questions will provide further insight into the role of oxidative stress in CB chemoreceptors in the manifestation of an enhanced chemoreflex in CHF.In conclusion, the study by Ding et al. (2) clearly provides novel evidence to suggest that MnSOD deficiency and elevated mitochondrial O2− level in glomus cells contributes to CB dysfunction in CHF. Nonetheless, since neither adenovirus CuZn-SOD (3) nor MnSOD (2) gene transfer to CB improves cardiac function in this model of CHF, therapeutic strategies aiming at protection of CB from oxidative stress in the treatment of CHF still await future validation.GRANTSThis work was supported in part by National Science Council, Taiwan, Republic of China Research Grants NSC97-2320-B-182A-007-MY3 and NSC98-2923-B-182A-001-MY3 (to S. H. H. Chan) and 98-2320-B075-B-002-MY3 (to J. Y. H. Chan).DISCLOSURESNo conflicts of interest are declared by the author(s).REFERENCES1. Ding Y , Li YL , Schultz HD . Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits. J Appl Physiol 105: 14– 23, 2008.Link | ISI | Google Scholar2. Ding Y , Li YL , Zimmerman MC , Schultz HD . Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits. Am J Physiol Regul Integr Comp Physiol (Nov 18, 2009). doi: 10.1152/ajpregu.00629.2009.ISI | Google Scholar3. Ding Y , Li YL , Zimmerman MC , Davisson RL , Schultz HD . Role of CuZn superoxide dismutase on carotid body function in heart failure rabbits. Cardiovasc Res 81: 678– 85, 2009.Crossref | PubMed | ISI | Google Scholar4. Kemp PJ . Detecting acute changes in oxygen: will the real sensor please stand up? Exp Physiol 91: 829– 834, 2006.Crossref | PubMed | ISI | Google Scholar5. Li YL , Schultz HD . Enhanced sensitivity of Kv channels to hypoxia in the rabbit carotid body in heart failure: role of angiotensin II. J Physiol 575: 215– 227, 2006.Crossref | PubMed | ISI | Google Scholar6. Li YL , Gao L , Zucker IH , Schultz HD . NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits. Cardiovasc Res 75: 546– 554, 2007.Crossref | PubMed | ISI | Google Scholar7. Li YL , Li YF , Liu D , Cornish KG , Patel KP , Zucker IH , Channon KM , Schultz HD . Gene transfer of neuronal nitric oxide synthase to carotid body reverses enhanced chemoreceptor function in heart failure rabbits. Circ Res 97: 260– 267, 2005.Crossref | PubMed | ISI | Google Scholar8. Li YL , Xia XH , Zheng H , Gao L , Li YF , Liu D , Patel KP , Wang W , Schultz HD . Angiotensin II enhances carotid body chemoreflex control of sympathetic outflow in chronic heart failure rabbits. Cardiovasc Res 71: 129– 138, 2006.Crossref | PubMed | ISI | Google Scholar9. Schultz HD , Li YL . Carotid body function in heart failure. Respir Physiol Neurobiol 157: 171– 185, 2007.Crossref | PubMed | ISI | Google Scholar10. Sun SY , Wang W , Zucker IH , Schultz HD . Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol 86: 1264– 1272, 1999.Link | ISI | Google Scholar11. Triposkiadis F , Karayannis G , Giamouzis G , Skoularigis J , Louridas G , Butler J . The sympathetic nervous system in heart failure. J Am Coll Cardiol 54: 1747– 1762, 2009.Crossref | PubMed | ISI | Google Scholar12. Wang WZ , Gao L , Wang HJ , Zucker IH , Wang W . Interaction between cardiac sympathetic afferent reflex and chemoreflex is mediated by the NTS AT1 receptors in heart failure. Am J Physiol Heart Circ Physiol 295: H1216– H1226, 2008.Link | ISI | Google Scholar13. Zucker IH , Wang W , Brandle M , Schultz HD , Patel KP . Neural regulation of sympathetic nerve activity in heart failure. Prog Cardiovasc Dis 37: 397– 414, 1995.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. Y. H. Chan, Dept. of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, 81346, Taiwan, Republic of China (e-mail: yhwa@isca.vghks.gov.tw). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 298Issue 2February 2010Pages R301-R302 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00792.2009PubMed20007512History Received 30 November 2009 Accepted 3 December 2009 Published online 1 February 2010 Published in print 1 February 2010 Metrics" @default.
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