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The Reciprocal Relationship Between Heme Oxygenase and Nitric Oxide Syn- Thase in the Organs of Lipopolysaccharide-Treated Rodents

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The Reciprocal Relationship Between Heme Oxygenase and Nitric Oxide Syn- Thase in the Organs of Lipopolysaccharide-Treated Rodents Biomedical Research 30 (4) 235-243, 2009 The reciprocal relationship between heme oxygenase and nitric oxide syn- thase in the organs of lipopolysaccharide-treated rodents Masayuki FURUICHI, Motoi YOKOZUKA, Ken TAKEMORI, Yoshitaka YAMANASHI and Atsuhiro SAKAMOTO All authors are affiliated with the Department of Anesthesiology, Nippon Medical School, Tokyo, Japan (Received 2 April 2009; and accepted 12 June 2009) Abstract The production of nitric oxide (NO) by inducible NO synthase (NOS) and carbon monoxide (CO) by inducible heme oxygenase (HO) contributes greatly to endotoxemia. Reciprocal relationships have been proposed between the NO/NOS and CO/HO systems. However, the interaction between these systems during endotoxemia is unclear, and it is unknown whether the interactive behavior differs among organs. Using endotoxic rats, we studied the effects of the inducible NOS (iNOS) inhibitor L-canavanine (CAN), and the HO inhibitor zinc protoporphyrin (ZPP) on gene expres- sion and protein levels of iNOS, endothelial NOS (eNOS), inducible HO (HO-1), and constitutive HO (HO-2) in the brain, lung, heart, liver and kidney tissue. Intravenous injection of LPS signifi- cantly increased iNOS and HO-1 gene expression in all organs. The effects of LPS on eNOS gene expression differed among organs, with increased expression in the liver and kidney, and no change in the lung, brain and heart. ZPP administration down-regulated the LPS-induced increase in HO-1 expression and produced a further increase in iNOS expression in all organs. These data suggest that the CO/HO system modifies the NO/NOS system in endotoxic organs, and that there were only minor organ-specific behaviors in terms of the relationship between these systems in the organs examined. Endotoxemia, which can lead to shock, is a detri- is produced by three distinct NOS enzymes. Two of mental consequence of severe Gram-negative bacte- these NOS isozymes are predominantly constitutive- rial infection. Endotoxic shock is initiated by the ly expressed in endothelial cells (eNOS) and in neu- release of bacterial cell wall-derived lipopolysaccha- ronal cells (nNOS), whereas the expression of the ride (LPS) and the subsequent production of third isozyme (iNOS) is inducible in a variety of cytokines and vasoactive mediators (13). Gaseous cells (e.g., macrophages, hepatocytes, vascular mediators, namely nitric oxide (NO) and carbon smooth muscle cells and cardiac myocytes) by nu- monoxide (CO), and the major endogenous sources merous stimuli, including LPS (5, 13). iNOS is re- of these mediators, nitric oxide synthase (NOS) and sponsible for producing most of the NO that causes heme oxygenase (HO), serve a pivotal role in endo- hypotension and oxidative stress during endotoxic toxemia. shock, while eNOS is reported to have only a minor NO is an extensively studied molecule, and is role in the pathophysiology of endotoxemia (9, 18). known for its vasorelaxation and oxidative stressor CO has been perceived for many years to be a properties during endotoxemia and septic shock. NO life-threatening gas; recently, however, CO has be- come recognized to have anti-inflammatory and va- Address correspondence to: Dr. Masayuki Furuichi sorelaxative properties and is essential for life. HO Department of Anesthesiology, Nippon Medical School, is the rate-limiting enzyme in the catabolism of 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan heme, a process that promotes the formation of Tel: +81-3-5814-6243, Fax: +81-3-5685-3077 equimolar amounts of the bile pigment biliverdin, E-mail: [email protected] free iron, and CO (1). Together with the anti-inflam- 236 M. Furuichi et al. matory and anti-oxidative functions of HO, the jected; the control (CON) group, in which vehicle CO/HO system has recently been recognized as a was administered instead of LPS; the LPS+CAN vasodilator as well as a cytoprotector. HO has two group, in which 10 mg/kg LPS was initially injected distinct isozymes. HO-1 is highly inducible by followed by a continuous infusion of 20 mg/kg/h heme and a vast array of non-heme substances, in- CAN; the LPS+ZPP group, in which an initial dose cluding LPS. By contrast, HO-2 is expressed in a of 10 mg/kg LPS was followed by hourly injections constitutive fashion, and appears to function as a of 0.1 μmol/kg/h ZPP; the CAN group, in which ini- heme-binding molecule in normal cells (19). The tial saline injection was followed by a continuous similarities and diversities of the NO/NOS and CO/ infusion of 20 mg/kg/h CAN; and the ZPP group, in HO systems were well established in numerous which the initial saline injection was followed by studies (11, 14), but the interactions between these hourly injections of 0.1 μmol/kg/h ZPP. Blood pres- systems have not yet been elucidated. The interac- sure and pulse rate were recorded at three time- tive behavior of the two systems has been examined points: immediately prior to the initial injection of in monocytic cells (7), vascular endothelial cells (4), LPS or saline, and 3 and 6 h after the injection. An- and vascular smooth muscle cells (22), and accumu- imals were decapitated after 6 h and the brains, lating evidence from these studies has shown that lungs, hearts, livers, and kidneys were extracted. All the NO/NOS system induces the CO/HO system, samples were stored at −80°C before determination while the CO/HO system reciprocally regulates the of mRNA expression and protein levels of HO-1, NO/NOS system. The relationship between the two HO-2, iNOS, and eNOS. The concentration of CAN systems in whole organs, on the other hand, has not and ZPP used in this study was confirmed by pre- been well studied, and it is unknown whether the liminary experiments and previous reports from our two systems interact in the same manner in all or- laboratory, which were titrated not to effect the gans or whether the two systems interact in an or- baseline enzymatic activity of NOS and HO, respec- gan-specific manner. tively, but only the LPS-regulated enzyme activity In this study, we examined the interactions be- (2, 15). tween the two systems in whole organs by measur- ing the expression of mRNA and protein for iNOS, Real-time reverse transcriptase-polymerase chain eNOS, HO-1, and HO-2 in LPS-treated rat brain, reaction (Real-time PCR). Total RNA was extracted lung, heart, liver, and kidney. We also administered from each organ using the chaotropic Trizol method L-canavanine (CAN), a selective iNOS inhibitor and followed by isogen-chloroform extraction and iso- zinc protoporphyrin (ZPP), an HO inhibitor, to de- propanol precipitation (3). The mRNA was reverse- termine the reciprocal relationship between the two transcribed using a High Capacity cDNA Reverse systems. Transcription Kit (Applied Biosystems Japan, To- kyo, Japan) and PCR Express (Thermo Fisher Sci- entific, Waltham, MA, USA). We used TaqMan® MATERIALS AND METHODS Gene Expression Assays (Applied Biosystems Ja- Animal treatment and organ preparation. Male Wi- pan) for real-time PCR primers and TaqMan fluoro- star rats aged 8–10 weeks, weighing 230–270 g, genic probes. The accession numbers of the primers were purchased from Saitama Experimental Animal and probes are presented in Table 1. A glyceralde- Supply (Saitama, Japan). The experimental protocol hyde-3-phosphate dehydrogenase (GAPDH) probe was approved by the Animal Experimental Ethical Review Committee of Nippon Medical School. Rats were anesthetized by an intravenous injection of Table. 1 Accession numbers of primers and probes (Ap- 50 mg/kg pentobarbital followed by continuous infu- plied Biosystems, Foster City, CA, USA) with NCBI RefSeq accession numbers for each target gene sion of 25 mg/kg/h. To ensure the airway remained Nitric oxide synthase 2 open, a polyethylene catheter was intubated into the Rn00561646-m1, NM_012611.3 trachea, and spontaneous ventilation of atmospheric (iNOS) Nitric oxide synthase 3 air was maintained throughout the study. To mea- Rn02132634-s1, NM_021838.2 surement of blood pressure, a polyethylene catheter (eNOS) Heme oxygenase 1 was inserted into the left femoral artery. Animals Rn00561387-m1, NM_012580.2 were assigned into six groups (n = 8 per group): the (HO-1) Heme oxygenase 2 lipopolysaccharide (LPS) group, in which 10 mg/kg Rn00577761-m1, NM_024387.1 LPS (5 mg/mL dissolved by normal saline) was in- (HO-2) Gaseous mediators in solid organs 237 and primer set (Pre-Developed TaqMan® Assay Re- of variance (ANOVA) and Bonferroni’s multiple- agents; Rat GAPD Endogenous control Probe, Prim- comparison tests were performed to determine dif- er Code number 4352338E, NCBI RefSeq accession ferences in gene expression between the CON and number NM_017008.3) (Applied Biosystems Japan) LPS groups. The same test was also performed to was purchased and included alongside the unknown distinguish differences in mean arterial pressure samples as an endogenous control. The relative (MAP) and pulse rate between the groups. Repeat- amounts of all mRNAs were measured using an ed-measures ANOVA and Bonferroni’s multiple- ABI 7500 Fast Real-Time PCR System (Applied comparison tests were performed to determine Biosystems Japan) and calculated by the compara- differences in MAP and pulse rate over time. P < tive CT method (Applied Biosystems, Foster City, 0.05 was considered to indicate a significant differ- CA, USA). ence. All statistical analyses were carried out using Dr. SPSS® (SPSS Inc. Chicago, IL). Data are ex- Immunoblotting. Protein expression was measured pressed as means ± standard deviation (SD). for the groups that showed a significant difference in mRNA expression. Protein was extracted from RESULTS homogenated organ samples showing average mRNA expression in each group. Samples were Figs. 1, 2 and 3 show the relative mRNA expression lysed with T-PER® (PIERCE, Rockford, IL) lysis of HO-1, iNOS, and eNOS, respectively.
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