Microvascular Actions of CO

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CO is a gaseous product of the HO reaction that utilizes molecular oxygen to oxidatively degrade protoheme IX into biliverdin-IXa, ferrous iron, and the gas. CO has been considered a gaseous mediator analogous to NO that activates soluble guanylate cyclase (sGC) as a common transducer to relax vascular systems. In mammals, HO exists in two forms: HO-1 and HO-2. HO-1 is induced by varied stressors such as cytokines, heavy metals, ROS and hypoxia. Excess NO could also cause the HO-1 induction. Microvascular actions of endogenously generated CO was first demonstrated in the liver [10]. Liver constitutes a major organ responsible for detoxification of the hemoglobin-derived heme and biliary excretion of bilirubin-IXa, a product generated from biliverdin-IXa through biliverdin reductase. We demonstrated intrahepatic distribution of two major HO isozymes immunohistochemically, with the finding that the two isozymes have distinct topographic patterns; HO-1, the inducible form, is expressed prominently in Kupffer cells, while the constitutive HO-2 is abundant in hepatocytes [11]. CO derived from HO-2 is necessary to keep sinusoids in a relaxing state through mechanisms involving sGC in hepatic stellate cells (HSC), also known as Ito cells, that constitute microvascular pericytes in this organ. HSC cultured on silicon membrane-coated dishes exhibited wrinkling formation through their intercellular connection of cytoplasmic processes and can respond to micromolar levels of CO to reduce the density of wrinkles, suggesting a relaxing response (Figure 2). Considering the microanatomical orientation of the liver cells in and around sinusoids, HO-2 in parenchyma stands in a reasonable position for the gas reception by HSC where CO released from hepatocytes can directly access to the cells and thereby modulate their contractility without being captured by hemoglobin in circulation. When exposed to disease conditions such as endotoxemia and advanced cirrhosis, liver could upregulate HO-1 in Kupffer cells and hepatocytes as a result of cytokine responses [12]. In experimental models of endo-toxemia, such an induction of HO-1 expands the ability of liver to degrade heme and to trigger overproduction of CO. Under these circumstances, CO turned out to contribute to maintenance of blood perfusion as well as that of bile excretion.

How can our neurovascular systems distinguish these two gases for sGC-mediated signaling events? As widely

Figure 2 Effects of CO on wrinkling formation of hepatic stellate cells in culture. The cells were cultured in dishes coated with a thin silicon membrane that displays wrinkles in response to spontaneous contraction of the cells. Note that the spontaneous wrinkles disappear in response to 15-minute superfusion of 10 ||mol/L CO.

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Figure 2 Effects of CO on wrinkling formation of hepatic stellate cells in culture. The cells were cultured in dishes coated with a thin silicon membrane that displays wrinkles in response to spontaneous contraction of the cells. Note that the spontaneous wrinkles disappear in response to 15-minute superfusion of 10 ||mol/L CO.

known, in the case of hemoglobin, CO stabilizes the six-coordinated form of the prosthetic heme and increases the affinity of molecular oxygen in other subunits, whereas NO binds to the a subunit of the heme and breaks the proximal histidine-Fe bond, forming a five-coordinated nitrosyl heme complex to decrease the affinity of oxygen in b subunits [13]. Similar to the case of hemoglobin, differences between NO and CO in the heme structure in the b-subunit of sGC appear to cause distinct activation states of the catalytic a-subunit of the enzyme. Because of such a structural difference in the heme coordination between NO and CO, the interaction of the two gases on the prosthetic heme of the enzyme leads to a unique regulatory response of the enzyme: Low tissue NO makes CO a modestly stimulatory modulator of the enzyme, whereas high tissue NO makes CO an inhibitory one. Observation that vascular smooth muscle cell-specific heme oxygenase-1 transgenic mice exhibit systemic hypertension rather than hypotension supports such a possibility [14]. This notion was also confirmed by our recent studies by showing that the interactions between the two gases cause fine-tuning of the sGC function in vivo [15]. In this study, we applied the newly developed monoclonal antibody (mAb) 3221 against sGC that can recognize the specific structure produced by the enzyme activation. Immunohistochemical analyses of rat retina where the background NO-generating activities appear het-erogenous among different neuronal layers revealed that light-induced upregulation of HO-1 activates sGC in retinal pigment epithelia (low NO), while it suppresses the enzyme in the inner plexiform layer (high NO). The physiological roles of CO in biological systems have not fully been investigated. However, distinct from NO, retina could benefit from the nonradical CO to maintain housekeeping cGMP without a risk of potential degradation of retinoids. Such a method of using CO is likely to be the case in relaxation of hepatic stellate cells to guarantee sinusoidal patency or in apoptotic control of spermatogenesis, where NO-breakable DNA or vitamin A is abundantly stored, respectively [16].

Glossary

Carbon monoxide: a gaseous monoxide produced through the breakdown of heme catalyzed by heme oxygenase.

Gas biology: a new concept proposed by authors. Anew research field that investigates biological functions of gaseous molecules produced and/or consumed in cells and tissues.

Nitric Oxide: a gaseous signal molecule produced by nitric oxide syn-thases. It has numerous functions including relaxation of vascular smooth muscle cells and neural signal transduction.

Oxygen sensing: the ability of biological systems to sense the changes of oxygen concentrations in and around the cells.

Oxyradical bioimaging: a method for real-time imaging of behavior of oxygen radicals such as superoxide anion and nitric oxide.

Acknowledgments

The authors acknowledge support by the 21st Century Center-of-Excellence Program and by the Leading Project for Biosimulation from the Ministry of Education, Sciences and Technology of Japan.

References

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5. Kashiwagi, S., Kajimura, M., Yoshimura, Y., and Suematsu, M. (2002). Nonendothelial source of nitric oxide in arterioles but not in venules: Alternative source revealed in vivo by diaminofluorescein microfluo-rography. Circ. Res. 91, e55-e64. The first quantitative demonstration of NO in microcirculation, suggesting its resource from circulation.

6. Prabhakar, N. R., Dinerman, J. L., Agani, F. H., and Snyder, S. H. (1995). Carbon monoxide: A role in carotid body chemoreception. Proc. Natl. Acad. Sci. USA 92, 1994-1997.

7. Semenza, G. L., Nejfelt, M. K., Chi, S. M., and Antonarakis, S. E. (1991). Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. Proc. Natl. Acad. Sci. USA 88, 5680-5684.

8. Maxwell, P. H., Wiesener, M. S., Chang, G. W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., and Ratcliffe, P. J. (1999) The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271-275.

9. Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., and Whitelaw, M. L. (2002). Asparagine hydroxylation of the HIF transactivation domain is a hypoxic switch. Science 295, 858-861.

10. Suematsu, M., Goda, N., Sano, T., Kashiwagi, S., Egawa, T., Shinoda, Y., and Ishimura, Y. (1995). Carbon monoxide: An endogenous modulator of sinusoidal tone in the perfused rat liver. J. Clin. Invest. 96, 2431-2437.

11. Goda, N., Suzuki, K., Naito, M., Takeoka, S., Tsuchida, E., Ishimura, Y., Tamatani, T., and Suematsu, M. (1998). Distribution of heme oxy-genase isoforms in rat liver: Topographic basis for carbon monoxide-mediated microvascular relaxation. J. Clin. Invest. 101, 604-612.

12. Kyokane, T., Norimizu, S., Taniai, H., Yamaguchi, T., Takeoka, S., Tsuchida, E., Naito, M., Nimura, Y., Ishimura, Y., and Suematsu, M. (2001). Carbon monoxide from heme catabolism protects against hepa-tobiliary dysfunction in endotoxin-treated rat liver. Gastroenterology 120, 1227-1240.

13. Yonetani, T., Tsuneshige, A., Zhou, Y., and Chen, X. (1998). Electron paramagnetic resonance and oxygen-binding studies of a-nitrosyl haemoglobin: A novel oxygen carrier having NO-assisted allosteric function. J. Biol. Chem. 273, 20323-20333.

14. Imai, T., Morita, T., Shindo, T., Nagai, R., Yazaki, Y., Kurihara, H., Suematsu, M., and Katayama, S. (2001). Vascular smooth muscle cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxide-induced vasodilation in mice. Circ. Res. 89, 55-62.

15. Kajimura, M., Shimoyama, M., Tsuyama, S., Suzuki, T., Kozaki, S., Takenaka, S., Tsubota, K., Oguchi, Y., and Suematsu, M. (2003). Visualization of gaseous monoxide reception by soluble guanylate cyclase in the rat retina. FASEB J. 17, 506-508.

16. Ozawa, N., Goda, N., Makino, N., Yamaguchi, T., Yoshimura, Y., and Suematsu, M. (2002). Leydig cell-derived heme oxygenase-1 regulates apoptosis of premetiotic germ cells in response to stress. J. Clin. Invest. 109, 457-467.

17. Suematsu, M. (2002). Gas biology: How do the gases conduct protein function in vivo? [in Japanese]. Seikagaku 74, 1317-1328.

Further Reading

Semenza, G. L. (2001). HIF-1, O2, and 3PHDs: How animal cells signal hypoxia to the nucleus. Cell 107, 1-3. An excellent review of hypoxia-sensing mechanisms.

Suematsu, M., and Ishimura, Y. (2000). The heme oxygenase-carbon monoxide system: A regulator of hepatobiliary function. Hepatology 31, 3-6. A concise summary to understand CO-mediated regulatory mechanisms for hepatic microcirculation.

2001. He was the winner of the first Lafon Microcirculation Award in 1995. His laboratory primarily focuses on gas biology, which handles the molecular basis of gaseous signal transduction and its pathophysiologic implications.

Dr. Goda is an assistant professor in the same department who has organized a project for analyses of HIF-1a conditional knock out mice.

Dr. Suematsu is a leader of the National Leading Project for Biosimulation assisted by metabolome analyses.

Capsule Biography

Dr. Suematsu has headed the Department of Biochemistry and Integrative Medical Biology at the Keio University School of Medicine since

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