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Peterson SJ, Dave N, Kothari J. The Effects of Heme Oxygenase Upregulation on Obesity and the Metabolic Syndrome. Antioxid Redox Signal 2020; 32:1061-1070. [PMID: 31880952 DOI: 10.1089/ars.2019.7954] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Obesity is a chronic condition that is characterized by inflammation and oxidative stress with consequent cardiovascular complications of hypertension, dyslipidemia, and vascular dysfunction. Obesity-induced metabolic syndrome remains an epidemic of global proportions. Recent Advances: Gene targeting of the endothelium with a retrovirus using an endothelium-specific promoter vascular endothelium cadherin (VECAD)-HO-1 offers a potential long-term solution to adiposity by targeting the endothelium. This has resulted in improvements of both vascular function and adiposity attenuation. Critical Issues: Heme oxygenase plays an ever-increasing role in the understanding of human biology in the complex conditions of obesity and the metabolic syndrome. The heme oxygenase 1 (HO-1) system creates biliverdin/bilirubin, which functions as an antioxidant, and carbon monoxide, which has antiapoptotic properties. Future Directions: Upregulation of HO-1 has been shown to improve adiposity as well as vascular function in both animal and human studies.
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Affiliation(s)
- Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, New York.,New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York
| | - Niel Dave
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York
| | - Janish Kothari
- New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, New York
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Drummond HA, Mitchell ZL, Abraham NG, Stec DE. Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease. Antioxidants (Basel) 2019; 8:antiox8060181. [PMID: 31216709 PMCID: PMC6617021 DOI: 10.3390/antiox8060181] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 06/13/2019] [Accepted: 06/15/2019] [Indexed: 12/13/2022] Open
Abstract
Heme oxygenase (HO) plays an important role in the cardiovascular system. It is involved in many physiological and pathophysiological processes in all organs of the cardiovascular system. From the regulation of blood pressure and blood flow to the adaptive response to end-organ injury, HO plays a critical role in the ability of the cardiovascular system to respond and adapt to changes in homeostasis. There have been great advances in our understanding of the role of HO in the regulation of blood pressure and target organ injury in the last decade. Results from these studies demonstrate that targeting of the HO system could provide novel therapeutic opportunities for the treatment of several cardiovascular and renal diseases. The goal of this review is to highlight the important role of HO in the regulation of cardiovascular and renal function and protection from disease and to highlight areas in which targeting of the HO system needs to be translated to help benefit patient populations.
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Affiliation(s)
- Heather A Drummond
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MI 39216, USA.
| | - Zachary L Mitchell
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MI 39216, USA.
| | - Nader G Abraham
- Departments of Medicine and Pharmacology, New York Medical College, Vahalla, NY 10595, USA.
- Joan C. Edwards School of Medicine, Marshall University, Huntington, VA 25701, USA.
| | - David E Stec
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MI 39216, USA.
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3
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Babu D, Leclercq G, Motterlini R, Lefebvre RA. Differential Effects of CORM-2 and CORM-401 in Murine Intestinal Epithelial MODE-K Cells under Oxidative Stress. Front Pharmacol 2017; 8:31. [PMID: 28228725 PMCID: PMC5296622 DOI: 10.3389/fphar.2017.00031] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 01/16/2017] [Indexed: 12/14/2022] Open
Abstract
Carbon monoxide (CO)-releasing molecules (CO-RMs) are intensively studied to provide cytoprotective and anti-inflammatory effects of CO in inflammatory conditions including intestinal inflammation. The water-soluble CORM-A1 reduced apoptosis and NADPH oxidase (NOX)-derived reactive oxygen species (ROS) induced by tumor necrosis factor (TNF)-α/cycloheximide (CHX) in mouse MODE-K intestinal epithelial cells (IECs), without influencing TNF-α/CHX-induced mitochondrial superoxide anion (O2•–). The aim of the present study in the same model was to comparatively investigate the influence of lipid-soluble CORM-2 and water-soluble CORM-401, shown in vitro to release more CO under oxidative conditions. CORM-2 abolished TNF-α/CHX-induced total cellular ROS whereas CORM-401 partially reduced it, both partially reducing TNF-α/CHX-induced cell death. Only CORM-2 increased mitochondrial O2•– production after 2 h of incubation. CORM-2 reduced TNF-α/CHX-, rotenone- and antimycin-A-induced mitochondrial O2•– production; CORM-401 only reduced the effect of antimycin-A. Co-treatment with CORM-401 during 1 h exposure to H2O2 reduced H2O2 (7.5 mM)-induced ROS production and cell death, whereas CORM-2 did not. The study illustrates the importance of the chemical characteristics of different CO-RMs. The lipid solubility of CORM-2 might contribute to its interference with TNF-α/CHX-induced mitochondrial ROS signaling, at least in mouse IECs. CORM-401 is more effective than other CO-RMs under H2O2-induced oxidative stress conditions.
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Affiliation(s)
- Dinesh Babu
- Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium
| | - Georges Leclercq
- Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium
| | - Roberto Motterlini
- INSERM U955, Faculty of Medicine, Equipe 12 and University Paris Est Créteil, France
| | - Romain A Lefebvre
- Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium
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4
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Babu D, Leclercq G, Motterlini R, Lefebvre RA. Differential Effects of CORM-2 and CORM-401 in Murine Intestinal Epithelial MODE-K Cells under Oxidative Stress. Front Pharmacol 2017. [PMID: 28228725 DOI: 10.3389/fphar.2017.00031/bibtex] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2023] Open
Abstract
Carbon monoxide (CO)-releasing molecules (CO-RMs) are intensively studied to provide cytoprotective and anti-inflammatory effects of CO in inflammatory conditions including intestinal inflammation. The water-soluble CORM-A1 reduced apoptosis and NADPH oxidase (NOX)-derived reactive oxygen species (ROS) induced by tumor necrosis factor (TNF)-α/cycloheximide (CHX) in mouse MODE-K intestinal epithelial cells (IECs), without influencing TNF-α/CHX-induced mitochondrial superoxide anion ([Formula: see text]). The aim of the present study in the same model was to comparatively investigate the influence of lipid-soluble CORM-2 and water-soluble CORM-401, shown in vitro to release more CO under oxidative conditions. CORM-2 abolished TNF-α/CHX-induced total cellular ROS whereas CORM-401 partially reduced it, both partially reducing TNF-α/CHX-induced cell death. Only CORM-2 increased mitochondrial [Formula: see text] production after 2 h of incubation. CORM-2 reduced TNF-α/CHX-, rotenone- and antimycin-A-induced mitochondrial [Formula: see text] production; CORM-401 only reduced the effect of antimycin-A. Co-treatment with CORM-401 during 1 h exposure to H2O2 reduced H2O2 (7.5 mM)-induced ROS production and cell death, whereas CORM-2 did not. The study illustrates the importance of the chemical characteristics of different CO-RMs. The lipid solubility of CORM-2 might contribute to its interference with TNF-α/CHX-induced mitochondrial ROS signaling, at least in mouse IECs. CORM-401 is more effective than other CO-RMs under H2O2-induced oxidative stress conditions.
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Affiliation(s)
- Dinesh Babu
- Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium
| | - Georges Leclercq
- Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium
| | - Roberto Motterlini
- INSERM U955, Faculty of Medicine, Equipe 12 and University Paris Est Créteil, France
| | - Romain A Lefebvre
- Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University Ghent, Belgium
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Gupta N, Singh T, Chaudhary R, Garg SK, Sandhu GS, Mittal V, Gupta R, Bodin R, Sule S. Bilirubin in coronary artery disease: Cytotoxic or protective? World J Gastrointest Pharmacol Ther 2016; 7:469-476. [PMID: 27867680 PMCID: PMC5095566 DOI: 10.4292/wjgpt.v7.i4.469] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 07/07/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
Bilirubin has traditionally been considered a cytotoxic waste product. However, recent studies have shown bilirubin to have anti-oxidant, anti-inflammatory, vasodilatory, anti-apoptotic and anti-proliferative functions. These properties potentially confer bilirubin a new role of protection especially in coronary artery disease (CAD), which is a low grade inflammatory process exacerbated by oxidative stress. In fact, recent literature reports an inverse relationship between serum concentration of bilirubin and the presence of CAD. In this article, we review the current literature exploring the association between levels of bilirubin and risk of CAD. We conclude that current evidence is inconclusive regarding the protective effect of bilirubin on CAD. A causal relationship between low serum bilirubin level and increased risk of CAD is not currently established.
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Abstract
Heme oxygenases are composed of two isozymes, Hmox1 and Hmox2, that catalyze the degradation of heme to carbon monoxide (CO), ferrous iron, and biliverdin, the latter of which is subsequently converted to bilirubin. While initially considered to be waste products, CO and biliverdin/bilirubin have been shown over the last 20 years to modulate key cellular processes, such as inflammation, cell proliferation, and apoptosis, as well as antioxidant defense. This shift in paradigm has led to the importance of heme oxygenases and their products in cell physiology now being well accepted. The identification of the two human cases thus far of heme oxygenase deficiency and the generation of mice deficient in Hmox1 or Hmox2 have reiterated a role for these enzymes in both normal cell function and disease pathogenesis, especially in the context of cardiovascular disease. This review covers the current knowledge on the function of both Hmox1 and Hmox2 at both a cellular and tissue level in the cardiovascular system. Initially, the roles of heme oxygenases in vascular health and the regulation of processes central to vascular diseases are outlined, followed by an evaluation of the role(s) of Hmox1 and Hmox2 in various diseases such as atherosclerosis, intimal hyperplasia, myocardial infarction, and angiogenesis. Finally, the therapeutic potential of heme oxygenases and their products are examined in a cardiovascular disease context, with a focus on how the knowledge we have gained on these enzymes may be capitalized in future clinical studies.
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Affiliation(s)
- Anita Ayer
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
| | - Abolfazl Zarjou
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
| | - Anupam Agarwal
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
| | - Roland Stocker
- Vascular Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, Australia; and Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Alabama
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Stec DE, Juncos LA, Granger JP. Renal intramedullary infusion of tempol normalizes the blood pressure response to intrarenal blockade of heme oxygenase-1 in angiotensin II-dependent hypertension. ACTA ACUST UNITED AC 2016; 10:346-51. [PMID: 26922123 DOI: 10.1016/j.jash.2016.01.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 01/22/2016] [Accepted: 01/24/2016] [Indexed: 12/28/2022]
Abstract
Previous studies have demonstrated that intramedullary inhibition of heme oxygenase-1 (HO-1) increases the blood pressure and superoxide production response to angiotensin II (Ang II) infusion. The present study was designed to test the hypothesis that increased renal medullary superoxide production contributes to the increase in blood pressure in response to blockade of renal medullary HO-1 in Ang II-induced hypertension. Male C57BL/6J mice (16-24 weeks of age) were implanted with chronic intrarenal medullary interstitial (IRMI) and infused with: saline, tempol (6 mM), the HO-1 inhibitor QC-13 (25 μM), or a combination of tempol + QC-13. Tempol treatment was started 2 days before infusion of QC-13. After 2 days, Ang II was infused subcutaneously at a rate of 1 μg/kg/min for 10 days. Blood pressures on days 7-10 of Ang II infusion alone averaged 150 ± 3 mm Hg in mice receiving IRMI infusion of saline. IRMI infusion of QC-13 increased blood pressure in Ang II-treated mice to 164 ± 2 (P < .05). Renal medullary superoxide production in Ang II-treated mice was significantly increased by infusion of QC-13 alone. Ang II-treated mice receiving IRMI infusion of tempol had a blood pressure of 136 ± 3 mm Hg. Ang II-treated mice receiving IRMI infusion of tempol and QC-13 had a significantly lower blood pressure (142 ± 2 mm Hg, P < .05) than mice receiving QC-13 alone. The increase in renal medullary superoxide production was normalized by infusion of tempol alone or in combination with QC-13. These results demonstrate that renal medullary interstitial blockade of HO-1 exacerbates Ang II-induced hypertension via a mechanism that is dependent on enhanced superoxide generation and highlight the important antioxidant function of HO-1 in the renal medulla.
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Affiliation(s)
- David E Stec
- Department of Physiology and Biophysics, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA.
| | - Luis A Juncos
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Joey P Granger
- Department of Physiology and Biophysics, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, USA
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Babu D, Leclercq G, Goossens V, Remijsen Q, Vandenabeele P, Motterlini R, Lefebvre RA. Antioxidant potential of CORM-A1 and resveratrol during TNF-α/cycloheximide-induced oxidative stress and apoptosis in murine intestinal epithelial MODE-K cells. Toxicol Appl Pharmacol 2015; 288:161-78. [PMID: 26187750 DOI: 10.1016/j.taap.2015.07.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/03/2015] [Accepted: 07/07/2015] [Indexed: 12/26/2022]
Abstract
Targeting excessive production of reactive oxygen species (ROS) could be an effective therapeutic strategy to prevent oxidative stress-associated gastrointestinal inflammation. NADPH oxidase (NOX) and mitochondrial complexes (I and II) are the major sources of ROS production contributing to TNF-α/cycloheximide (CHX)-induced apoptosis in the mouse intestinal epithelial cell line, MODE-K. In the current study, the influence of a polyphenolic compound (resveratrol) and a water-soluble carbon monoxide (CO)-releasing molecule (CORM-A1) on the different sources of TNF-α/CHX-induced ROS production in MODE-K cells was assessed. This was compared with H2O2-, rotenone- or antimycin-A-induced ROS-generating systems. Intracellular total ROS, mitochondrial-derived ROS and mitochondrial superoxide anion (O2(-)) production levels were assessed. Additionally, the influence on TNF-α/CHX-induced changes in mitochondrial membrane potential (Ψm) and mitochondrial function was studied. In basal conditions, CORM-A1 did not affect intracellular total or mitochondrial ROS levels, while resveratrol increased intracellular total ROS but reduced mitochondrial ROS production. TNF-α/CHX- and H2O2-mediated increase in intracellular total ROS production was reduced by both resveratrol and CORM-A1, whereas only resveratrol attenuated the increase in mitochondrial ROS triggered by TNF-α/CHX. CORM-A1 decreased antimycin-A-induced mitochondrial O2(-) production without any influence on TNF-α/CHX- and rotenone-induced mitochondrial O2(-) levels, while resveratrol abolished all three effects. Finally, resveratrol greatly reduced and abolished TNF-α/CHX-induced mitochondrial depolarization and mitochondrial dysfunction, while CORM-A1 only mildly affected these parameters. These data indicate that the cytoprotective effect of resveratrol is predominantly due to mitigation of mitochondrial ROS, while CORM-A1 acts solely on NOX-derived ROS to protect MODE-K cells from TNF-α/CHX-induced cell death. This might explain the more pronounced cytoprotective effect of resveratrol.
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Affiliation(s)
- Dinesh Babu
- Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, Belgium.
| | - Georges Leclercq
- Department of Clinical Chemistry, Microbiology and Immunology, Faculty of Medicine and Health Sciences, Ghent University, Belgium
| | - Vera Goossens
- Inflammation Research Center, Molecular Signaling and Cell Death Unit, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Molecular Signaling and Cell Death Unit, Ghent University, Ghent, Belgium
| | - Quinten Remijsen
- Inflammation Research Center, Molecular Signaling and Cell Death Unit, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Molecular Signaling and Cell Death Unit, Ghent University, Ghent, Belgium
| | - Peter Vandenabeele
- Inflammation Research Center, Molecular Signaling and Cell Death Unit, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Molecular Signaling and Cell Death Unit, Ghent University, Ghent, Belgium
| | - Roberto Motterlini
- Inserm U955, Equipe 12 and University Paris-Est Créteil, Faculty of Medicine, F-94000 Créteil, France
| | - Romain A Lefebvre
- Heymans Institute of Pharmacology, Faculty of Medicine and Health Sciences, Ghent University, Belgium
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Lee TM, Lin SZ, Chang NC. Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling. Free Radic Biol Med 2014; 77:71-81. [PMID: 25224036 DOI: 10.1016/j.freeradbiomed.2014.08.022] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Revised: 07/28/2014] [Accepted: 08/20/2014] [Indexed: 11/19/2022]
Abstract
Glycogen synthase kinase-3 (GSK-3) signaling has been shown to play a role in the regulation of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of antioxidant genes, including heme oxygenase-1 (HO-1). We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction, a status of high reactive oxygen species (ROS), by attenuating nerve growth factor (NGF) expression and whether Nrf2/HO-1 signaling is involved in the protection. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats were treated for 4 weeks. The postinfarction period was associated with increased oxidative-nitrosative stress, as measured by myocardial superoxide, nitrotyrosine, and dihydroethidium fluorescent staining. In concert, myocardial norepinephrine levels and immunohistochemical analysis of sympathetic nerve revealed a significant increase in innervation in vehicle-treated rats compared with sham-operated rats. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those in sham. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administration of LiCl. LiCl stimulated the nuclear translocation of Nrf2 and the transactivation of the Nrf2 target gene HO-1. Inhibition of phosphoinositide 3-kinase by wortmannin reduced the increase in Nrf2 nucleus translocation and HO-1 expression compared with lithium alone. In addition, the lithium-attenuated NGF levels were reversed in the presence of the Nrf2 inhibitor trigonelline, HO-1 inhibitor SnPP, and peroxynitrite generator SIN-1, indicating the role of Nrf2/HO-1/ROS. In conclusion, lithium protects against ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via antioxidant activation of the Nrf2/HO-1 axis.
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Affiliation(s)
- Tsung-Ming Lee
- Cardiology Section, Department of Medicine, China Medical University-An Nan Hospital, Tainan 709, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shinn-Zong Lin
- Neuropsychiatry Center, China Medical University Hospital, Taichung, Taiwan; Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; Department of Neurosurgery, China Medical University-An Nan Hospital, Tainan 709, Taiwan; Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan
| | - Nen-Chung Chang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
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Gentile G, Mastroluca D, Ruggenenti P, Remuzzi G. Novel effective drugs for diabetic kidney disease? or not? Expert Opin Emerg Drugs 2014; 19:571-601. [PMID: 25376947 DOI: 10.1517/14728214.2014.979151] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Diabetes mellitus is increasingly common worldwide and is expected to affect 592 million people by 2035. The kidney is often involved. A key goal in treating diabetes is to reduce the risk of development of kidney disease and, if kidney disease is already present, to delay the progression to end-stage renal disease (ESRD). This represents a social and ethical issue, as a significant proportion of patients reaching ESRD in developing countries do not have access to renal replacement therapy. AREAS COVERED The present review focuses on novel therapeutic approaches for diabetic nephropathy (DN), implemented on the basis of recent insights on its pathophysiology, which might complement the effects of single inhibition of the renin-angiotensin-aldosterone system (RAAS), the cornerstone of renoprotective interventions in diabetes, along with glycemic and blood pressure control. EXPERT OPINION Although a plethora of new treatment options has arisen from experimental studies, the number of novel renoprotective molecules successfully implemented in clinical practice over the last two decades is disappointingly low. Thus, new investigational strategies and diagnostic tools - including the appropriate choice of relevant renal end points and the study of urinary proteome of patients - will be as important as new therapeutic interventions to fight DN. Finally, in spite of huge financial interests in replacing the less expensive ACE inhibitors and angiotensin II receptor blockers with newer drugs, any future therapeutic approach has to be tested on top of - rather than instead of - optimal RAAS blockade.
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Affiliation(s)
- Giorgio Gentile
- IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò" , Villa Camozzi, Via Giambattista Camozzi 3, 24020, Ranica, Bergamo , Italy +39 03545351 ; +39 0354535371 ;
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Ju TJ, Kwon WY, Kim YW, Kim JY, Kim YD, Lee IK, Park SY. Hemin Improves Insulin Sensitivity in Skeletal Muscle in High Fat–Fed Mice. J Pharmacol Sci 2014; 126:115-25. [DOI: 10.1254/jphs.14003fp] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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Ren Y, D'Ambrosio MA, Garvin JL, Wang H, Carretero OA. Mechanism of inhibition of tubuloglomerular feedback by CO and cGMP. Hypertension 2013; 62:99-104. [PMID: 23648700 DOI: 10.1161/hypertensionaha.113.01164] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Tubuloglomerular feedback (TGF) is a mechanism that senses NaCl in the macula densa (MD) and causes constriction of the afferent arteriole. CO, either endogenous or exogenous, inhibits TGF at least in part via cGMP. We hypothesize that CO in the MD, acting via both cGMP-dependent and -independent mechanisms, attenuates TGF by acting downstream from depolarization and calcium entry into the MD cells. In vitro, microdissected rabbit afferent arterioles and their MD were simultaneously perfused and TGF was measured as the decrease in afferent arteriole diameter. MD depolarization was induced with ionophores, while adding the CO-releasing molecule-3 to the MD perfusate at nontoxic concentrations. CO-releasing molecule-3 blunted depolarization-induced TGF at 50 μmol/L, from 3.6±0.4 to 2.5±0.4 µm (P<0.01), and abolished it at 100 μmol/L, to 0.1±0.1 μm (P<0.001; n=6). When cGMP generation was blocked by guanylyl cyclase inhibitor LY83583 added to the MD, CO-releasing molecule-3 no longer affected depolarization-induced TGF at 50 μmol/L (2.9±0.4 versus 3.0±0.4 µm) but partially inhibited TGF at 100 μmol/L (to 1.3±0.2 μm; P<0.05; n=9). Experiments using eicosatetraynoic acid and indomethacin suggest arachidonic acid metabolites do not mediate the cGMP-independent effect of CO. We then added the calcium ionophore A23187 to the MD, which caused TGF (4.1±0.6 μmol/L); A23187-induced TGF was inhibited by CO-releasing molecule-3 at 50 μmol/L (1.9±0.6 μmol/L; P<0.01) and 100 μmol/L (0.2±0.5 μmol/L; P<0.001; n=6). We conclude that CO inhibits TGF acting downstream from depolarization and calcium entry, acting via cGMP at low concentrations, but additional mechanisms of action may be involved at higher concentrations.
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Affiliation(s)
- Yilin Ren
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA
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Csongradi E, Juncos LA, Drummond HA, Vera T, Stec DE. Role of carbon monoxide in kidney function: is a little carbon monoxide good for the kidney? Curr Pharm Biotechnol 2012; 13:819-26. [PMID: 22201605 DOI: 10.2174/138920112800399284] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2010] [Accepted: 08/28/2010] [Indexed: 12/13/2022]
Abstract
Carbon monoxide (CO) is an endogenously produced gas resulting from the degradation of heme by heme oxygense or from fatty acid oxidation. Heme oxygenase (HO) enzymes are constitutively expressed in the kidney (HO-2) and HO-1 is induced in the kidney in response to several physiological and pathological stimuli. While the beneficial actions of HO in the kidney have been recognized for some time, the important role of CO in mediating these effects has not been fully examined. Recent studies using CO inhalation therapy and carbon monoxide releasing molecules (CORMs) have demonstrated that increases in CO alone can be beneficial to the kidney in several forms of acute renal injury by limiting oxidative injury, decreasing cell apoptosis, and promoting cell survival pathways. Renal CO is also emerging as a major regulator of renal vascular and tubular function acting to protect the renal vasculature against excessive vasoconstriction and to promote natriuresis by limiting sodium reabsorption in tubule cells. Within this review, recent studies on the physiological actions of CO in the kidney will be explored as well as the potential therapeutic avenues that are being developed targeting CO in the kidney which may be beneficial in diseases such as acute renal failure and hypertension.
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Affiliation(s)
- Eva Csongradi
- Department of Physiology & Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216, USA
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Wei S, Gao C, Wei G, Chen Y, Zhong L, Li X. The level of serum bilirubin associated with coronary lesion types in patients with coronary artery disease. J Cardiovasc Med (Hagerstown) 2012; 13:432-8. [PMID: 21799439 DOI: 10.2459/jcm.0b013e32834a3967] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Serum bilirubin has been proven to be associated with coronary artery disease (CAD). However, how serum bilirubin is related to the complexity of coronary artery lesions is still unknown. METHODS AND RESULTS One thousand two hundred and sixty patients (men 775, 61.5%, mean age, 59.3 ± 8.2 years) diagnosed with unstable angina were enrolled in the study. Patients were categorized into three major groups and group III was further divided into four subgroups according to the guidelines of AHA/ACC 1993 described in the Methods section. The total serum bilirubin levels showed significant differences among the three major groups (group I vs. group II, 14.8 ± 5.8 vs. 13.7 ± 4.7 μmol/l, P=0.017; group I vs. group III, 14.8 ± 5.8 vs. 12.6 ± 4.4 μmol/l, P<0.001; group II vs. group III, 13.7 ± 4.7 vs. 12.6 ± 4.4 μmol/l, P=0.009). The difference was further seen among the subgroups. Logistic regression analysis demonstrated that age, male sex, histories of hypertension and diabetes, and total serum bilirubin were independent risk factors for CAD. However, in the subgroups, only age, male sex, history of hypertension and total serum bilirubin were associated with CAD. Total serum bilirubin showed the strongest relationship (odds ratio=0.95, 95% confidence interval 0.91-0.98, P=0.001). CONCLUSION Total serum bilirubin level is an independent risk factor for CAD. It has a strong relationship with coronary artery lesion types.
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Affiliation(s)
- Shipeng Wei
- Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
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15
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Ren Y, D'Ambrosio MA, Wang H, Falck JR, Peterson EL, Garvin JL, Carretero OA. Mechanisms of carbon monoxide attenuation of tubuloglomerular feedback. Hypertension 2012; 59:1139-44. [PMID: 22508834 DOI: 10.1161/hypertensionaha.112.192120] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Carbon monoxide (CO) is a physiological messenger with diverse functions in the kidney, including controlling afferent arteriole tone both directly and via tubuloglomerular feedback (TGF). We have reported that CO attenuates TGF, but the mechanisms underlying this effect remain unknown. We hypothesized that CO, acting via cGMP, cGMP-dependent protein kinase, and cGMP-stimulated phosphodiesterase 2, reduces cAMP in the macula densa, leading to TGF attenuation. In vitro, microdissected rabbit afferent arterioles and their attached macula densa were simultaneously perfused. TGF was measured as the decrease in afferent arteriole diameter elicited by switching macula densa NaCl from 10 to 80 mmol/L. Adding a CO-releasing molecule (CORM-3, 5 × 10(-5) mol/L) to the macula densa blunted TGF from 3.3 ± 0.3 to 2.0 ± 0.3 μm (P<0.001). The guanylate cyclase inhibitor LY-83583 (10(-6) mol/L) enhanced TGF (5.8 ± 0.6 μm; P<0.001 versus control) and prevented the effect of CORM-3 on TGF (LY-83583+CORM-3, 5.5 ± 0.3 μm). Similarly, the cGMP-dependent protein kinase inhibitor KT-5823 (2 × 10(-6) mol/L) enhanced TGF and prevented the effect of CORM-3 on TGF (KT-5823, 6.0 ± 0.7 μm; KT-5823+CORM-3, 5.9 ± 0.8 μm). However, the phosphodiesterase 2 inhibitor BAY-60-7550 (10(-6) mol/L) did not prevent the effect of CORM-3 on TGF (BAY-60-7550, 4.07 ± 0.31 μm; BAY-60-7550+CORM-3, 1.84 ± 0.31 μm; P<0.001). Finally, the degradation-resistant cAMP analog dibutyryl-cAMP (10(-3) mol/L) prevented the attenuation of TGF by CORM-3 (dibutyryl-cAMP, 4.6 ± 0.5 μm; dibutyryl-cAMP+CORM-3, 5.0 ± 0.6 μm). We conclude that CO attenuates TGF by reducing cAMP via a cGMP-dependent pathway mediated by cGMP-dependent protein kinase rather than phosphodiesterase 2. Our results will lead to a better understanding of the mechanisms that control the renal microcirculation.
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Affiliation(s)
- Yilin Ren
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA
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16
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Stec DE, Drummond HA, Gousette MU, Storm MV, Abraham NG, Csongradi E. Expression of heme oxygenase-1 in thick ascending loop of henle attenuates angiotensin II-dependent hypertension. J Am Soc Nephrol 2012; 23:834-41. [PMID: 22323644 DOI: 10.1681/asn.2011050455] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Kidney-specific induction of heme oxygenase-1 (HO-1) attenuates the development of angiotensin II (Ang II) -dependent hypertension, but the relative contribution of vascular versus tubular induction of HO-1 is unknown. To determine the specific contribution of thick ascending loop of Henle (TALH) -derived HO-1, we generated a transgenic mouse in which the uromodulin promoter controlled expression of human HO-1. Quantitative RT-PCR and confocal microscopy confirmed successful localization of the HO-1 transgene to TALH tubule segments. Medullary HO activity, but not cortical HO activity, was significantly higher in transgenic mice than control mice. Enhanced TALH HO-1 attenuated the hypertension induced by Ang II delivered by an osmotic minipump for 10 days (139 ± 3 versus 153 ±2 mmHg in the transgenic and control mice, respectively; P<0.05). The lower blood pressure in transgenic mice associated with a 60% decrease in medullary NKCC2 transporter expression determined by Western blot. Transgenic mice also exhibited a 36% decrease in ouabain-sensitive sodium reabsorption and a significantly attenuated response to furosemide in isolated TALH segments. In summary, these results show that increased levels of HO-1 in the TALH can lower blood pressure by a mechanism that may include alterations in NKCC2-dependent sodium reabsorption.
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Affiliation(s)
- David E Stec
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, 39216, USA.
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Renal Inhibition of Heme Oxygenase-1 Increases Blood Pressure in Angiotensin II-Dependent Hypertension. Int J Hypertens 2011; 2012:497213. [PMID: 22164328 PMCID: PMC3227477 DOI: 10.1155/2012/497213] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Accepted: 09/06/2011] [Indexed: 01/31/2023] Open
Abstract
The goal of this study was to test the hypothesis that renal medullary heme oxygenase (HO) acts as a buffer against Ang-II dependent hypertension. To test this hypothesis, renal medullary HO activity was blocked using QC-13, an imidazole-dioxolane HO-1 inhibitor, or SnMP, a classical porphyrin based HO inhibitor. HO inhibitors were infused via IRMI catheters throughout the study starting 3 days prior to implantation of an osmotic minipump which delivered Ang II or saline vehicle. MAP was increased by Ang II infusion and further increased by IRMI infusion of QC-13 or SnMP. MAP averaged 113 ± 3, 120 ± 7, 141 ± 2, 153 ± 2, and 154 ± 3 mmHg in vehicle, vehicle + IRMI QC-13, Ang II, Ang II + IRMI QC-13, and Ang II + IRMI SnMP treated mice, respectively (n = 6). Inhibition of renal medullary HO activity with QC-13 in Ang II infused mice was also associated with a significant increase in superoxide production as well as significant decreases in antioxidant enzymes catalase and MnSOD. These results demonstrate that renal inhibition of HO exacerbates Ang II dependent hypertension through a mechanism which is associated with increases in superoxide production and decreases in antioxidant enzymes.
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Hosick PA, Stec DE. Heme oxygenase, a novel target for the treatment of hypertension and obesity? Am J Physiol Regul Integr Comp Physiol 2011; 302:R207-14. [PMID: 22071158 DOI: 10.1152/ajpregu.00517.2011] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Heme oxygenase (HO) is the rate-limiting enzyme in the metabolism of heme-releasing bioactive molecules carbon monoxide (CO), biliverdin, and iron, each with beneficial cardiovascular actions. Biliverdin is rapidly reduced to bilirubin, a potent antioxidant, by the enzyme biliverdin reductase, and iron is rapidly sequestered by ferritin in the cell. Several studies have demonstrated that HO-1 induction can attenuate the development of hypertension as well as lower blood pressure in established hypertension in both genetic and experimental models. HO-1 induction can also reduce target organ injury and can be beneficial in cardiovascular diseases, such as heart attack and stroke. Recent studies have also identified a beneficial role for HO-1 in the regulation of body weight and metabolism in diabetes and obesity. Chronic HO-1 induction lowers body weight and corrects hyperglycemia and hyperinsulinemia. Chronic HO-1 induction also modifies the phenotype of adipocytes in obesity from one of large, cytokine producing to smaller, adiponectin producing. Finally, chronic induction of HO-1 increases oxygen consumption, CO(2), and heat production and activity in obese mice. This review will discuss the current understanding of the actions of the HO system to lower blood pressure and body weight and how HO or its metabolites may be ideal candidates for the development of drugs that can both reduce blood pressure and lower body weight.
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Affiliation(s)
- Peter A Hosick
- Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, Jackson, MS 39216, USA
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19
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Hosick PA, Stec DE. Heme oxygenase, a novel target for the treatment of hypertension and obesity? AMERICAN JOURNAL OF PHYSIOLOGY. REGULATORY, INTEGRATIVE AND COMPARATIVE PHYSIOLOGY 2011. [PMID: 22071158 DOI: 10.1152/ajpregu.00517.20113349392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Heme oxygenase (HO) is the rate-limiting enzyme in the metabolism of heme-releasing bioactive molecules carbon monoxide (CO), biliverdin, and iron, each with beneficial cardiovascular actions. Biliverdin is rapidly reduced to bilirubin, a potent antioxidant, by the enzyme biliverdin reductase, and iron is rapidly sequestered by ferritin in the cell. Several studies have demonstrated that HO-1 induction can attenuate the development of hypertension as well as lower blood pressure in established hypertension in both genetic and experimental models. HO-1 induction can also reduce target organ injury and can be beneficial in cardiovascular diseases, such as heart attack and stroke. Recent studies have also identified a beneficial role for HO-1 in the regulation of body weight and metabolism in diabetes and obesity. Chronic HO-1 induction lowers body weight and corrects hyperglycemia and hyperinsulinemia. Chronic HO-1 induction also modifies the phenotype of adipocytes in obesity from one of large, cytokine producing to smaller, adiponectin producing. Finally, chronic induction of HO-1 increases oxygen consumption, CO(2), and heat production and activity in obese mice. This review will discuss the current understanding of the actions of the HO system to lower blood pressure and body weight and how HO or its metabolites may be ideal candidates for the development of drugs that can both reduce blood pressure and lower body weight.
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Affiliation(s)
- Peter A Hosick
- Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, Jackson, MS 39216, USA
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20
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Wang H, Garvin JL, D'Ambrosio MA, Falck JR, Leung P, Liu R, Ren Y, Carretero OA. Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo. Am J Physiol Heart Circ Physiol 2011; 300:H1320-6. [PMID: 21239629 DOI: 10.1152/ajpheart.01118.2010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Tubuloglomerular feedback (TGF) is a renal autoregulatory mechanism that constricts the afferent arteriole in response to increases in distal NaCl. Heme oxygenases (HO-1 and HO-2) release carbon monoxide (CO) and biliverdin, which may help control renal function. We showed in vitro that HO products inhibit TGF; however, we do not know whether this also occurs in vivo or the mechanism(s) involved. We hypothesized that in vivo HO-1 and HO-2 in the nephron inhibit TGF via release of CO and biliverdin. We first performed laser capture microdissection followed by real-time PCR and found that both HO-1 and HO-2 are expressed in the macula densa. We next performed micropuncture experiments in vivo on individual rat nephrons, adding different compounds to the perfusate, and found that an HO inhibitor, stannous mesoporphyrin (SnMP), potentiated TGF (P < 0.05, SnMP vs. control). The CO-releasing molecule (CORM)-3 partially inhibited TGF at 50 μmol/l (P < 0.01, CORM-3 vs. control) and blocked it completely at higher doses. A soluble guanylyl cyclase (sGC) inhibitor, LY83583, blocked the inhibitory effect of CORM-3 on TGF. Biliverdin also partially inhibited TGF (P < 0.01, biliverdin vs. control), most likely attributable to decreased superoxide (O(2)(-)) because biliverdin was rendered ineffective by tempol, a O(2)(-) dismutase mimetic. We concluded that HO-1 and HO-2 in the nephron inhibit TGF by releasing CO and biliverdin. The inhibitory effect of CO on TGF is mediated by the sGC/cGMP signaling pathway, whereas biliverdin probably acts by reducing O(2)(-).
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Affiliation(s)
- Hong Wang
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA
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21
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Nath KA, Hernandez MC, Croatt AJ, Katusic ZS, Juncos LA. Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II. Am J Physiol Regul Integr Comp Physiol 2010; 299:R1183-91. [PMID: 20702802 PMCID: PMC2980457 DOI: 10.1152/ajpregu.00212.2010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2010] [Accepted: 08/09/2010] [Indexed: 02/07/2023]
Abstract
ANG II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II-exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury.
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Affiliation(s)
- Karl A Nath
- Division of Nephrology and Hypertension, Mayo Clinic, Guggenheim 542, 200 First St., SW, Rochester, MN 55905, USA.
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Young SC, Storm MV, Speed JS, Kelsen S, Tiller CV, Vera T, Drummond HA, Stec DE. Inhibition of biliverdin reductase increases ANG II-dependent superoxide levels in cultured renal tubular epithelial cells. Am J Physiol Regul Integr Comp Physiol 2009; 297:R1546-53. [PMID: 19759334 DOI: 10.1152/ajpregu.90933.2008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Induction of heme oxygenase-1 (HO-1) in the renal medulla increases carbon monoxide and bilirubin production and decreases ANG II-mediated superoxide production. The goal of this study was to determine the importance of increases in bilirubin to the antioxidant effects of HO-1 induction in cultured mouse thick ascending loop of Henle (TALH) and inner medullary collecting duct (IMCD3) cells. Bilirubin levels were decreased by using small interfering RNAs (siRNAs) targeted to biliverdin reductase (BVR), which is the cellular enzyme responsible for the conversion of biliverdin to bilirubin. Treatment of cultured TALH or IMCD-3 cells with BVR siRNA (50 or 100 nM) resulted in an 80% decrease in the level of BVR protein and decreased cellular bilirubin levels from 46 +/- 5 to 23 +/- 4 nM (n = 4). We then determined the effects of inhibition of BVR on ANG II-mediated superoxide production. Superoxide production induced by ANG II (10(-9) M) significantly increased in both TALH and IMCD-3 cells. Treatment of TALH cells with BVR siRNA resulted in a significant increase in ouabain-sensitive rubidium uptake from 95 +/- 6 to 122 +/- 5% control (n = 4, P < 0.05). Lastly, inhibition of BVR with siRNA did not prevent the decrease in superoxide levels observed in cells pretreated with the HO-1 inducer, hemin. We conclude that decreased levels of cellular bilirubin increase ANG II-mediated superoxide production and sodium transport; however, increases in bilirubin are not necessary for HO-1 induction to attenuate ANG II-mediated superoxide production.
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Affiliation(s)
- Shelby C Young
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA
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Vera T, Granger JP, Stec DE. Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG II-dependent hypertension in mice. Am J Physiol Regul Integr Comp Physiol 2009; 297:R738-43. [PMID: 19571206 DOI: 10.1152/ajpregu.90889.2008] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Population studies indicate that moderate hyperbilirubinemia is associated with reduced incidence of cardiovascular diseases, including hypertension. Despite this correlative evidence, no studies have directly tested the hypothesis that moderate increases in plasma bilirubin levels can attenuate the development of hypertension. This hypothesis was tested by treating mice with Indinavir, a drug that competes with bilirubin for metabolism by UDP-glucuronosyltransferase 1A1 (UGT1A1). Treatment of mice with Indinavir (500 mg x kg(-1) x day(-1), gavage) resulted in a twofold increase in plasma unconjugated bilirubin levels. Next, we determined the effect of Indinavir-induced changes in plasma bilirubin on the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia was induced 3 days before the implantation of an osmotic minipump that delivered ANG II at a rate of 1 microg x kg(-1) x min(-1). ANG II infusion increased mean arterial pressure (MAP) by 20 mmHg in control mice but by only 6 mmHg in mice treated with Indinavir (n = 6). Similar to Indinavir treatment, direct infusion of bilirubin (37.2 mg x kg(-1) x day(-1) i.v.) resulted in a twofold increase in plasma bilirubin levels and also attenuated the development of ANG II-dependent hypertension. Moderate hyperbilirubinemia resulted in an increase in plasma nitrate/nitrite levels, which averaged 36 +/- 2 vs. 50 +/- 7 microM in ANG II vehicle vs. Indinavir-treated mice (n = 5). Moderate hyperbilirubinemia resulted in attenuation of vascular oxidative stress as determined by dihydroethidium staining of aortic segments. These results indicate that moderate hyperbilirubinemia prevents ANG II-dependent hypertension by a mechanism that may involve decreases in vascular oxidative stress.
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Affiliation(s)
- Trinity Vera
- Dept. of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA.
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Vera T, Kelsen S, Stec DE. Response to Use of Protoporphyrins to Evaluate Heme Oxygenase Problematical. Hypertension 2009. [DOI: 10.1161/hypertensionaha.108.125583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Trinity Vera
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Miss
| | - Siliva Kelsen
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Miss
| | - David E. Stec
- Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Miss
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