Effects of protoporphyrins on production of nitric oxide and expression of vascular endothelial growth factor in vascular smooth muscle cells and macrophages.
Languages of publication
Heme oxygenase-1 (HO-1), an inducible enzyme degrading heme to biliverdin, iron and carbon monoxide, is involved in regulation of inflammation and angiogenesis. Tin protoporphyrin (SnPPIX) and zinc protoporphyrin (ZnPPIX) are commonly used as competitive inhibitors of HO-1. We aimed to compare the effects of SnPPIX and ZnPPIX on the production of vascular endothelial growth factor (VEGF), activity of inducible nitric oxide synthase (iNOS) and cell viability. All experiments were performed on rat vascular smooth muscle cells and murine RAW264.7 macrophages treated with 3-10 μM protoporphyrins. Some cells were additionally stimulated with IL-1β or with lipopolysaccharide. After a 24 h incubation period SnPPIX and ZnPPIX significantly reduced the generation of VEGF in vascular smooth muscle cells and RAW264.7, both in resting and stimulated cells. The inhibitory potentials of both protoporphyrins on VEGF synthesis were very similar. In contrast, analysis of iNOS activity revealed that results obtained with different HO-1 inhibitors are discrepant. Generation of nitric oxide by iNOS was significantly increased by SnPPIX but strongly decreased by ZnPPIX. Similar differences were observed when cell viability was compared. SnPPIX improved the cell survival rate, whereas the same doses of ZnPPIX exerted some cytotoxic effects. In summary, SnPPIX and ZnPPIX can be used as HO-1 inhibitors in some experimental models. However, these compounds produce also HO-independent effects, which can make the interpretation of experiments very uncertain. Thus the involvement of the HO-1 pathway should be always confirmed by more specific methods.
- Anderson KE, Simionatto CS, Drummond GS, Kappas A. (1984) Tissue distribution of tin protoporphyrin, a potent competitive inhibitor of heme oxygenase. J Pharmacol Exp Ther.; 228: 327-33.
- Anderson KE, Simionatto CS, Drummond GS, Kappas A. (1986) Disposition of tin-protoporphyrin and suppression of hyperbilirubinemia in humans. Clin Pharmacol Ther.; 39: 510-20.
- Appleton SD, Chretien ML, McLaughlin BE, Vreman HJ, Stevenson DK, Brien JF, Nakaatsu K, Maurice DH, Marks GS. (1999) Selective inhibition of heme oxygenase, without inhibition of nitric oxide synthase or soluble guanylyl cyclase by metalloporphyrins at low concentrations. Drug Metab Dispos.; 27: 1214-9.
- Beri R, Chandra R. (1993) Chemistry and biology of heme. Effect of metal salts, organometals, and metalloporphyrins on heme synthesis and catabolism, with special reference to clinical implications and interactions with cytochrome P-450. Drug Metab Rev.; 25: 49-52.
- Bishop A, Marquis JC, Cashman NR, Demple B. (1999) Adaptive resistance to nitric oxide in motor neurons. Free Radic Biol Med.; 26: 978-86.
- Cavicchi M, Gibbs L, Whittle BJ. (2000) Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme and nitric oxide donors. Gut.; 47: 771-8.
- Chandra R, Upadhyaya G, Dass SK, Jain R. (2000) Co-administration of melatonin reverses the tin-protoporphyrin (SnPP) induced decline of cytochrome P450 content in vivo in rats. Eur J Drug Metab Pharmacokinet.; 25: 213-8.
- Chen YC, Shen SC, Lee WR, Lin HY, Ko CK, Lee TJ. (2002) Nitric oxide and prostaglandin E2 participate in lipopolysaccharide/interferon-gamma-induced heme oxygenase-1 and prevent RAW264.7 macrophages from UV-irradiation-induced cell death. J Cell Biochem.; 86: 331-9.
- Chernick RJ, Martasek P, Levere RD, Margreiter R, Abraham NG. (1989) Sensitivity of human tissue heme oxygenase to a new synthetic metalloporphyrin. Hepatology.; 10: 365-9.
- Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, Beppu T, Shibahara S, Ogawa M, Maeda H. (1999) Induction of heme oxygenase-1, nitric oxide and ischemia in experimental solid tumors and implication for tumor growth. Br J Cancer.; 80: 1945-54.
- Drummond GS. (1987) Control of heme oxygenase metabolism by synthetic metalloporphyrins. Ann NY Acad Sci.; 514: 87-95.
- Dulak J, Jozkowicz A, Foresti R, Green C, Motterlini R. (1999) Regulation of nitric oxide synthesis by heme oxygenase-1 in rat vascular smooth muscle cells. In Nitric oxide biology, part VII. Moncada S, Gustafsson L, Wiklund P, Higgs EA, eds, p 135. Portland Press, New York.
- Dulak J, Jozkowicz A, Foresti R, Kasza A, Frick M, Huk I, Green CJ, Pachinger O, Weidinger F, Motterlini R. (2002a) Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells. Antioxid Redox Signal.; 4: 229-40.
- Dulak J, Motterlini R, Huk I, Pachinger O, Weidinger F, Jozkowicz A. (2002b) Carbon monoxide and iron, by-products of heme oxygenase, modulate vascular endothelial growth factor synthesis in vascular smooth muscle cells. In: Physiology and pathology of heme oxygenase. Abraham N, Alam J, Nath K, eds, pp 97-107. Kluwer Academic/Plenum Publishers, New York.
- Foresti R, Clark JE, Green CJ, Motterlini RJ. (1997) Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J Biol Chem.; 272: 18411-7.
- Greenbaum NL, Kappas A. (1991) Comparative photoactivity of tin and zinc porphyrin inhibitors of heme oxygenase: pronounced photolability of the zinc compounds. Photochem Photobiol.; 54: 183-92.
- Grunemar L, Ny L. (1997) Pitfalls using metalloporphyrins in carbon monoxide research. Trends Pharmacol Sci.; 18: 193-5.
- Jozkowicz A, Dulak J, Piatkowska E, Placha W, Dembinska-Kiec A. (2000) Ligands of peroxisome proliferator-activated receptor-gamma increase the generation of vascular endothelial growth factor in vascular smooth muscle cells and in macrophages. Acta Biochim Polon.; 47: 1147-57.
- Jozkowicz A, Huk I, Nigisch A, Weigel G, Weidinger F, Dulak J. (2002) Effect of prostaglandin-J2 on VEGF synthesis depends on the induction of heme oxygenase-1. Antioxid Redox Signal.; 4: 577-85.
- Kampfer H, Kolb N, Manderscheid M, Wetyler C, Pfeilschifter J, Frank S. (2001) Macrophage-derived heme-oxygenase-1: expression, regulation, and possible function in skin repair. Mol Med.; 7: 488-98.
- Koh J, Suh SW, Gwag BJ, He Y, Hsu CY, Choi DW (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science.; 272: 1013-6.
- Kreiser D, Nguen X, Wong R, Seidman D, Stevenson D, Quan S, Abraham N, Dennery P. (2002) Heme oxygenase modulates fetal growth in the rat. Lab Invest.; 82: 687-92.
- Linden DJ, Narasimhan K, Gurfel D. (1993) Protoporphyrins modulate voltage-gated Ca current in AtT-20 pituitary cells. J Neurophysiol.; 70: 2673-7.
- Luo D, Vincent SR. (1994) Metalloporphyrins inhibit nitric oxide-dependent cGMP formation in vivo. Eur J Pharmacol.; 267: 263-7.
- Lutton JD, Abraham NG, Drummond GS, Levere RD, Kappas A. (1997) Zinc porphyrins: potent inhibitors of hematopoieses in animal and human bone marrow. Proc Natl Acad Sci U S A.; 94: 1432-6.
- Marton LS, Wang X, Kowalczuk A, Zhang ZD, Windmeyer E, Macdonald RL. (2000) Effects of hemoglobin on heme oxygenase gene expression and viability of cultured smooth muscle cells. Am J Physiol Heart Circ Physiol.; 279: H2405-13.
- Morse D, Choi AM. (2002) Heme oxygenase-1: the emerging molecule has arrived. Am J Respir Cell Mol Biol.; 27: 8-16.
- Polte T, Oberle S, Schroder H. (1997) The nitric oxide donor SIN-1 protects endothelial cells from tumor necrosis factor-alpha-mediated cytotoxicity: possible role for cyclic GMP and heme oxygenase. J Mol Cell Cardiol.; 29: 3305-10.
- Polte T, Abate A, Dennery PA, Schroder H. (2000) Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide. Arterioscler Thromb Vasc Biol.; 20: 1209-15.
- Quato MK, Maines MD. (1985) Prevention of neonatal hyperbilirubinemia in non-human primates by Zn-protoporphyrin. Biochem J.; 226: 51-7.
- Regan RF, Guo Y, Kumar N. (2000) Heme oxygenase-1 induction protects murine cortical astrocytes from hemoglobin toxicity. Neurosci Lett.; 282: 1-4.
- Sakaguchi S, Iizuka Y, Furasawa S, Ishikawa M, Satoh S, Takayanagi M. (2002) Role of Zn(2+) in oxidative stress caused by endotoxin challenge. Eur J Pharmacol.; 451: 309-16.
- Serfass L, Burstyn JN. (1998) Effect of heme oxygenase inhibitors on soluble guanylyl cyclase activity. Arch Biochem Biophys.; 359: 8-16.
- Snyder SH, Baranano DE. (2001) Heme oxygenase: a font with multiple messengers. Neuropsychopharmacology.; 25: 294-8.
- Steffensrud S. (1998) Tin metalloporphyrins: an answer to neonatal jaundice. Neonatal Netw.; 17: 11-7.
- Tamion F, Richard V, Bonmarchand G, Leroy J, Lebreton JP, Thuillez C. (2001) Induction of heme-oxygenase-1 prevents the systemic responses to hemorrhagic shock. Am J Respir Crit Care Med.; 164: 1933-8.
- Vreman HJ, Ekstrand BC, Stevenson DK. (1993) Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity. Pediatr Res.; 33: 195-200.
- Vreman HJ, Cipkala DA, Stevenson DK. (1996) Characterization of porphyrin heme oxygenase inhibitors. Can J Physiol Pharmacol.; 74: 278-85.
- Weiss G, Lutton JD, Fuchs D, Werner-Felmayer G, Bock G, Abraham NG, Kappas A, Levere RD, Wachter H. (1993) Comparative effects of heme and metalloporphyrins on interferon-gamma-mediated pathways in monocytic cells (THP-1). Proc Soc Exp Biol Med.; 202: 470-5.
- White KA, Marletta MA. (1992) Nitric oxide synthase is a cytochrome P-450 type hemoprotein. Biochemistry.; 31: 6627-31.
- Wolff DJ, Naddelman RA, Lubeskie A, Saks DA. (1996) Inhibition of nitric oxide synthase isoforms by porphyrins. Arch Biochem Biophys.; 333: 27-34.
- Zakhary R, Gaine SP, Dinerman JL, Ruat M, Flavahan NA, Snyder SH. (1996) Heme oxygenase-2: Endothelial and neuronal localization and role in endothelium-dependent relaxation. Proc Natl Acad Sci U S A.; 93: 795-8.
Publication order reference