Targeting heme oxygenase: Therapeutic implications for diseases of the cardiovascular system

Cardiology in Review

Volumn 17, Issue 3, 2009, Pages 99-111

  Peterson, Stephen J ^a,b   Frishman, William H ^a  

^a WESTCHESTER MEDICAL CENTER   (United States)

^b NEW YORK MEDICAL COLLEGE   (United States)

Author keywords

Bilirubin; Carbon monoxide; Circulating endothelial cells; Diabetes; Heme oxygenase; Hypertension

Indexed keywords

ACETYLSALICYLIC ACID; ADENOVIRUS VECTOR; ADIPONECTIN; ADVANCED GLYCATION END PRODUCT; ANGIOTENSIN II; ATACIGUAT; ATRIAL NATRIURETIC FACTOR; BILIRUBIN; BILIVERDIN; CARDIOVASCULAR AGENT; HEME OXYGENASE; HEME OXYGENASE 1; HEME OXYGENASE 2; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOSARTAN; METALLOPORPHYRIN; MEVINOLIN; NITRIC OXIDE DONOR; PROBUCOL; RESVERATROL; RIOCIQUAT 10; SIMVASTATIN; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; ENZYME ACTIVATOR; REACTIVE OXYGEN METABOLITE;

ANTIANGIOGENIC ACTIVITY; ANTIHYPERTENSIVE ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ATHEROSCLEROSIS; BLOOD VESSEL INJURY; CARDIOVASCULAR DISEASE; CELL CYCLE G2 PHASE; CELL CYCLE M PHASE; CELL CYCLE PROGRESSION; CELL CYCLE S PHASE; CELL DAMAGE; CELL PROLIFERATION; CORONARY ARTERY ATHEROSCLEROSIS; CORONARY RISK; DIABETES MELLITUS; DNA DAMAGE; DRUG EFFECT; ENDOTHELIUM CELL; ENDOTHELIUM INJURY; EXPERIMENTAL THERAPY; GENE OVEREXPRESSION; GENE TARGETING; GENE TRANSFER; GILBERT DISEASE; HEART INFARCTION; HEART INFARCTION SIZE; HEART MUSCLE ISCHEMIA; HEART PROTECTION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; ISCHEMIC PRECONDITIONING; LIPOPROTEIN BLOOD LEVEL; NONHUMAN; PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY; PROTEIN BLOOD LEVEL; PROTEIN TARGETING; QT PROLONGATION; RENAL PROTECTION; RESTENOSIS; REVIEW; SMOOTH MUSCLE FIBER; SPONTANEOUSLY HYPERTENSIVE RAT; TISSUE INJURY; UPREGULATION; VASODILATATION; VIRAL GENE DELIVERY SYSTEM; ANIMAL; DISEASE MODEL; ENZYMOLOGY; GENE THERAPY; GENETICS; METABOLISM; PHYSIOLOGY;

ANIMALS; CARDIOVASCULAR DISEASES; DISEASE MODELS, ANIMAL; ENZYME ACTIVATORS; GENE THERAPY; HEME OXYGENASE (DECYCLIZING); HUMANS; REACTIVE OXYGEN SPECIES; UP-REGULATION;

EID: 67549134935     PISSN: 10615377     EISSN: None     Source Type: Journal    
DOI: 10.1097/CRD.0b013e31819d813a     Document Type: Review

References (223)

1. Abraham NG, Drummond GS, Lutton JD, et al. The biological significance and physiological role of heme oxygenase. Cell Physiol Biochem. 1996;6: 129-168.
2. Cruse I, Maines MD. Evidence suggesting that the two forms of heme oxygenase are products of different genes. J Biol Chem. 1988;263:3348-3353.
3. Huang TJ, McCoubrey WK Jr, Maines MD. Heme oxygenase-2 interaction with metalloporphyrins: function of heme regulatory motifs. Antioxid Redox Signal. 2001;3:685- 696.
4. Scapagnini G, D'Agata V, Calabrese V, et al. Gene expression profiles of heme oxygenase isoforms in the rat brain. Brain Res. 2002;954:51-59.
5. Ishikawa K, Takeuchi N, Takahashi S, et al. Heme oxygenase-2. Properties of the heme complex of the purified tryptic fragment of recombinant human heme oxygenase-2. J Biol Chem. 1995;270:6345- 6350.
6. Abraham NG, da Silva JL, Lavrovsky Y, et al. Adenovirus-mediated heme oxygenase-1 gene transfer into rabbit ocular tissues. Invest Ophthalmol Vis Sci. 1995;36:2202-2210.
7. Abraham NG, Lavrovsky Y, Schwartzman ML, et al. Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity. Proc Natl Acad Sci USA. 1995;92:6798-6802.
8. + stem cells. Exp Hematol. 1996;24:1053.
9. Mingone CJ, Gupte SA, Chow JL, et al. Protoporphyrin IX generation from delta-aminolevulinic acid elicits pulmonary artery relaxation and soluble guanylate cyclase activation. Am J Physiol Lung Cell Mol Physiol. 2006; 291:L337-L344.
10. Yang L, Quan S, Nasjletti A, et al. Heme oxygenase-1 gene expression modulates angiotensin II-induced increase in blood pressure. Hypertension. 2004;43:1221-1226.
11. Lavrovsky Y, Schwartzman ML, Levere RD, et al. Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci USA. 1994;91: 5987-5991.
12. Dennery PA, Spitz DR, Yang G, et al. Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest. 1998;101:1001-1011.
13. Kappas A, Drummond G. Control of heme metabolism with synthetic metalloporphyrins. J Clin Invest. 1986;77:335-339.
14. Drummond GS, Kappas A. The cytochrome P-450-depleted animal: an experimental model for in vivo studies in chemical biology. Proc Natl Acad Sci USA. 1982;79:2384 -2388.
15. Kappas A. A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 2004;113: 119-123.
16. Vile GF, Basu-Modak S, Wlatner C, et al. Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts. Proc Natl Acad Sci USA. 1994;91:2607-2610.
17. Wagener FA, da Silva JL, Farley T, et al. Differential effects of heme oxygenase isoforms on heme mediation of endothelial intracellular adhesion molecule 1 expression. J Pharmacol Exp Ther. 1999;291:416-423.
18. Balla G, Jacob HS, Balla J, et al. Ferritin: a cytoprotective antioxidant strategm of endothelium. J Biol Chem. 1992;267:18148 -18153.
19. Hayashi S, Takamiya R, Yamaguchi T, et al. Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. Circ Res. 1999;85:663- 671.
20. Platt JL, Nath KA. Heme oxygenase: protective gene or Trojan horse. Nat Med. 1998;4:1364 -1365.
21. Nath KA, Haggard JJ, Croatt AJ, et al. The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo. Am J Pathol. 2000;156:1527-1535.
22. Stocker R, Yamamoto Y, McDonagh AF, et al. Bilirubin is an antioxidant of possible physiological importance. Science. 1987;235:1043-1046.
23. Stocker R, McDonagh AF, Glazer AN, et al. Antioxidant activities of bile pigments: biliverdin and bilirubin. Methods Enzymol. 1990;186: 301-309.
24. Wiesel P, Patel AP, DiFonzo N, et al. Endotoxin-induced mortality is related to increased oxidative stress and end-organ dysfunction, not refractory hypotension, in heme oxygenase-1-deficient mice. Circulation. 2000;102: 3015-3022.
25. Abraham NG, Kushida T, McClung J, et al. Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Circ Res. 2003;93:507-514.
26. Abraham NG, Rezzani R, Rodella L, et al. Overexpression of human heme oxygenase-1 attenuates endothelial cell sloughing in experimental diabetes. Am J Physiol Heart Circ Physiol. 2004;287:H2468-H2477.
27. Moqattash S, Lutton JD, bu-Hijleh MF, et al. Hemopoietic recovery from AZT toxicity with recombinant hemoglobin in a murine model of AIDS. Acta Haematol. 1994;92:182-186.
28. Otterbein LE, Kolls JK, Mantell LL, et al. Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J Clin Invest. 1999;103:1047-1054.
29. Leffler CW, Nasjletti A, Yu C, et al. Carbon monoxide and cerebral microvascular tone in newborn pigs. Am J Physiol. 1999;276:H1641-H1646.
30. Leffler CW, Nasjletti A, Johnson RA, et al. Contributions of prostacyclin and nitric oxide to carbon monoxide-induced cerebrovascular dilation in piglets. Am J Phyisiol Heart Circ Physiol. 2001;280:H1490-H1495.
31. Adachi T, Ishikawa K, Hida W, et al. Hypoxemia and blunted hypoxic ventilatory responses in mice lacking heme oxygenase-2. Biochem Biophys Res Commun. 2004;320:514 -522.
32. Kaide J-I, Zhang F, Wei Y, et al. Carbon monoxide of vascular origin attenuates the sensitivity of renal arterial vessels to vasoconstrictors. J Clin Invest. 2001;107:1163-1171.
33. Kaide J, Zhang F, Wei Y, et al. Vascular CO counterbalances the sensitizing influence of 20-HETE on agonist-induced vasoconstriction. Hypertension. 2004;44:210 -216.
34. Kaide J, Wang MH, Wang JS, et al. Transfection of CYP4A1 cDNA increases vascular reactivity in renal interlobar arteries. Am J Physiol Renal Physiol. 2003;284:F51-F56.
35. Perrella MA, Yet SF. Role of heme oxygenase-1 in cardiovascular function. Curr Pharm Des. 2003;9:2479 -2487.
36. Ferris CD, Jaffrey SR, Sawa A, et al. Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol. 1999;1:152-157.
37. Conners MS, Schultz MC, Dunn MW, et al. Hypoxia-induced complications of soft contact lens wear are alleviated by heme oxygenase induction. Invest Ophthalmol Vis Sci. 1992;33:780 -787.
38. Willis D, Moore AR, Frederick R, et al. Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med. 1996;2:87-90.
39. Laniado-Schwartzman M, Abraham NG, Conners M, et al. Heme oxygenase induction with attenuation of experimentally induced corneal inflammation. Biochem Pharmacol. 1997;53:1069 -1075.
40. Juan SH, Lee TS, Tseng KW, et al. Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2001;104:1519 -1525.
41. Ishikawa K, Navab M, Leitinger N, et al. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest. 1997;100:1209 -1216.
42. Wang LJ, Lee TS, Lee FY, et al. Expression of heme oxygenase-1 in atherosclerotic lesions. Am J Pathol. 1998;152:711-720.
43. Pileggi A, Molano RD, Berney T, et al. Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation. Diabetes. 2001;50:1983-1991.
44. Hashiba T, Suzuki M, Nagashima Y, et al. Adenovirus-mediated transfer of heme oxygenase-1 cDNA attenuates severe lung injury induced by the influenza virus in mice. Gene Ther. 2001;8:1499 -1507.
45. Amersi F, Buelow R, Kato H, et al. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest. 1999;104:1631-1639.
46. Guo Y, Stein AB, Wu WJ, et al. Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo. Am J Physiol Heart Circ Physiol. 2004;286:H1649-H1653.
47. Yet SF, Tian R, Layne MD, et al. Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res. 2001;89:168 -173.
48. Abraham NG, Kappas A. Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev. 2008;60:79 -127.
49. Abraham NG, Friedland ML, Levere RD. Heme metabolism in hepatic and erythroid cells. In: Brown E, ed. Progress in Hematology. Vol XIII ed. New York, NY: Grune and Stratton; 1983:75-130.
50. Schacter BA. Heme catabolism by heme oxygenase: physiology, regulation, and mechanism of action. Semin Hematol. 1988;25:349 -369.
51. Kushida T, LiVolti G, Goodman AI, et al. TNF-alpha-mediated cell death is attenuated by retrovirus delivery of human heme oxygenase-1 gene into human microvessel endothelial cells. Transplant Proc. 2002; 34:2973-2978.
52. Kushida T, Li Volti G, Quan S, et al. Role of human heme oxygenase-1 in attenuating TNF-alpha-mediated inflammation injury in endothelial cells. J Cell Biochem. 2002;87:377-385.
53. Stocker R, Glazer AN, Ames BN. Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci USA. 1987;84:5918 -5922.
54. Frei B, Stocker R, Ames BN. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci USA. 1988;85:9748 -9752.
55. Neuzil J, Stocker R. Free and albumin-bound bilirubin are efficient coantioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem. 1994;269:16712-16719.
56. Wu TW, Wu J, Li RK, et al. Albumin-bound bilirubins protect human ventricular myocytes against oxyradical damage. Biochem Cell Biol. 1991; 69:683- 688.
57. Dore S, Takahashi M, Ferris CD, et al. Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci USA. 1999;96:2445-2450.
58. Lleusy SF, Tomaro ML. Evidence of involvement of bilirubin as physiological protector against oxidative damage. Biochim Biophys Acta. 1994; 1223:9 -14.
59. Ossola JO, Tomaro ML. Heme oxygenase induction by cadmium chloride: evidence for oxidative stress involvement. Toxicology. 1995;104:141-147.
60. Ossola JO, Tomaro ML. Heme oxygenase induction by UVA radiation. A response to oxidative stress in rat liver. Int J Biochem Cell Biol. 1998;30: 285-292.
61. Clark JE, Foresti R, Green CJ, et al. Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem J. 2000;348(Pt 3):615- 619.
62. Clark JE, Foresti R, Sarathchandra P, et al. Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol Heart Circ Physiol. 2000;278:H643-H651.
63. Mazza F, Goodman A, Lombardo G, et al. Heme oxygenase-1 gene expression attenuates angiotensin II-mediated DNA damage in endothelial cells. Exp Biol Med (Maywood). 2003;228:576 -583.
64. Morita T, Imai T, Yamaguchi T, et al. Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: role of bilirubin and carbon monoxide generated by the enzyme. Antioxid Redox Signal. 2003;5:439-447.
65. Kwak JY, Takeshige K, Cheung BS, et al. Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free system. Biochim Biophys Acta. 1991;1076:369 -373.
66. Sano K, Nakamura H, Matsuo T. Mode of inhibitory action of bilirubin on protein kinase C. Pediatr Res 1985;19:587-590.
67. Rajagopalan S, Kurz S, Munzel T, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916 -1923.
68. Ishizaka N, Aizawa T, Mori I, et al. Heme oxygenase-1 is upregulated in the rat heart in response to chronic administration of angiotensin II. Am J Phyisiol Heart Circ Physiol. 2000;279:H672-H678.
69. Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics. 2004;113:1776 -1782.
70. Turkseven S, Kruger A, Mingone CJ, et al. Antioxidant mechanism of heme oxygenase-1 involves an increase in superoxide dismutase and catalase in experimental diabetes. Am J Physiol Heart Circ Physiol. 2005;289:H701-H707.
71. McClung JA, Morita T, Rodella L, et al. Heme oxygenase-1 prevents superoxide anion-associated vascular smooth muscle growth and decreases circulating endothelial cells in a rat model of balloon injury and restenosis in diabetes mellitus. Circulation. 2004;110:III-282.
72. Rezzani R, Quan S, Rodella L, et al. Heme oxygenase-1 upregulation attenuates glucose-mediated oxidative stress renal injury in HO-2 knockout mice [abstract]. Hypertension. 2003;42:86.
73. Milstien S, Katusic Z. Oxidation of tetrahydrobiopterin by peroxynitrite: implications for vascular endothelial function. Biochem Biophys Res Commun. 1999;263:681- 684.
74. Foresti R, Sarathchandra P, Clark JE, et al. Peroxynitrite induces haem oxygenase-1 in vascular endothelia to apoptosis. Biochem J. 1999;339:729-736.
75. Chang SH, Barbosa-Tessmann I, Chen C, et al. Glucose deprivation induces heme oxygenase-1 gene expression by a pathway independent of the unfolded protein response. J Biol Chem. 2002;277:1933-1940.
76. Mingone CJ, Turkseven S, Wolin MS, et al. Heme-oxygenase-1 modulates vascular responses in diabetic rats via guanylate cyclase activation: role of superoxide dismutase [abstract]. FASEB. 2005:8836.
77. Mansoor A, Mingone CJ, Turkseven S, et al. Down regulation of iNOS and in eNOS by overexpression of heme oxygenase-1 restore vascular response in diabetic rats. FASEB. 2005:7415.
78. Hill-Kapturczak N, Chang SH, Agarwal A. Heme oxygenase and the kidney. DNA Cell Biol. 2002;21:307-321.
79. Solari V, Piotrowska AP, Puri P. Expression of heme oxygenase-1 and endothelial nitric oxide synthase in the lung of newborns with congenital diaphragmatic hernia and persistent pulmonary hypertension. J Pediatr Surg. 2003;38:808-813.
80. Snyder SH, Baranano DE. Heme oxygenase: a font of multiple messengers. Neuropsychopharmacology. 2001;25:294 -298.
81. Motterlini R, Foresti R, Intaglietta M, et al. NO-mediated activation of heme oxgenase: endogenous cytoprotection against oxidative stress to endothelium. Am J Physiol. 1996;270:H107-H114.
82. Stanford SJ, Walters MJ, Hislop AA, et al. Heme oxygenase is expressed in human pulmonary artery smooth muscle where carbon monoxide has an anti-proliferative role. Eur J Pharmacol. 2003;473:135-141.
83. Ndisang JF, Tabien HE, Wang R. Carbon monoxide and hypertension. J Hypertens. 2004;22:1057-1074.
84. Ndisang JF, Wu L, Zhao W, et al. Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats. Blood. 2003;101:3893-3900.
85. Ou HS, Yang J, Dong LW, et al. Role of endogenous carbon monoxide in the pathogenesis of hypotension during septic shock. Sheng Li Xue Bao. 1999;51:1- 6.
86. Beltowski J, Jamroz A, Borkowska E. Heme oxygenase and carbon monoxide in the physiology and pathology of the cardiovascular system [in polish]. Postepy Hig Med Dosw (Online). 2004;58:83-99.
87. Ushiyama M, Morita T, Katayama S. Carbon monoxide regulates blood pressure cooperatively with nitric oxide in hypertensive rats. Heart Vessels. 2002;16:189 -195.
88. Togane Y, Morita T, Suematsu M, et al. Protective roles of endogenous carbon monoxide in neointimal development elicited by arterial injury. Am J Physiol Heart Circ Physiol. 2000;278:H623-H632.
89. Otterbein LE, Zuckerbraun BS, Haga M, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 2003;9:183-190.
90. Kukoba TV, Moibenko OO, Kotsioruba AV. Cardioprotective effect of heme oxygenase-1 induction by hemin on the isolated rat heart during ischemia - reperfusion in [Ukrainian]. Fiziol Zh. 2003;49:14 -21.
91. Yamada N, Yamaya M, Okinaga S, et al. Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema. Am J Hum Genet. 2000;66:187-195.
92. Tulis DA, Durante W, Liu X, et al. Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation. Circulation. 2001;104:2710 -2715.
93. Li Volti G, Wang J, Traganos F, et al. Differential effect of heme oxygenase-1 in endothelial and smooth muscle cell cycle progression. Biochem Biophys Res Commun. 2002;296:1077-1082.
94. Kushida T, Quan S, Yang L, et al. A significant role for the heme oxygenase-1 gene in endothelial cell cycle progression. Biochem Biophys Res Commun. 2002;291:68 -75.
95. Agarwal A, Balla J, Alam J, et al. Induction of heme oxygenase in toxic renal injury: a protective role in cisplatin nephrotoxicity in the rat. Kidney Int. 1995;48:1298 -1307.
96. Lutton JD, da Silva J-L, Moqattash S, et al. Differential induction of heme oxygenase in the hepatocarcinoma cell line (Hep3b) by environmental agents. J Cell Biochem. 1992;49:259 -265.
97. Kong D, Melo LG, Mangi AA, et al. Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation. 2004;109:1769 -1775.
98. Gu Y, Ortines R. Heme oxygenase-1 is cardioprotective in the remodeled, failing heart [abstract]. Circulation. 2004;110:III-201.
99. Seki T, Naruse M, Naruse K, et al. Induction of heme oxygenase produces load-independent cardioprotective effects in hypertensive rats. Life Sci. 1999;65:1077-1086.
100. Ooi H, Ito M, Pimental D. Heme oxygenase protects against β-adrenergic receptor-stimulated apoptosis in cardiac myocytes [abstract]. Circulation. 2004;110:III-5.
101. Kawamoto S, Flynn JP, Allen MD. Heme oxygenase-1 induction improves the viability of adult cardiomyocyte cellular grafts in vivo [abstract]. Circulation. 2004;110:III-302.
102. Tang YL, Tang Y, Zhang YC, et al. Mesenchymal stem cells protected with a hypoxia-regulated heme oxygenase-1 vector: a potential strategy to prevent graft cell death in the ischemic heart [abstract]. Circulation. 2004;110:III-3.
103. Motterlini R, Clark JE, Foresti R, et al. Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ Res. 2002;90:E17-E24.
104. Chatterjee PK. Water-soluble carbon monoxide-releasing molecules: helping to elucidate the vascular activity of the "silent killer." Br J Pharmacol. 2004;142:391-393.
105. Clark JE, Naughton P, Shurey S, et al. Cardioprotective actions by a watersoluble carbon monoxide-releasing molecule. Circ Res. 2003;93:e2-e8.
106. Foresti R, Hammad J, Clark JE, et al. Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br J Pharmacol. 2004;142:453- 460.
107. Wang R, Wang Z, Wu L. Carbon monoxide-induced vasorelaxation and the underlying mechanisms. Br J Pharmacol. 1997;121:927-934.
108. Morita T, Perrella MA, Lee M, et al. Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP. Proc Natl Acad Sci USA. 1995;92:1475-1479.
109. Ndisang JF, Wang R. Alterations in heme oxygenase/carbon monoxide system in pulmonary arteries in hypertension. Exp Biol Med (Maywood). 2003;228:557-563.
110. Levere RD, Martasek P, Escalante B, et al. Effect of heme arginate administration on blood pressure in spontaneously hypertensive rats. J Clin Invest. 1990;86:213-219.
111. Sammut IA, Foresti R, Clark JE, et al. Carbon monoxide is a major contributor to the regulation of vascular tone in aortas expressing high levels of haeme oxygenase-1. Br J Pharmacol. 1998;125:1437-1444.
112. Motterlini R, Mann BE, Johnson TR, et al. Bioactivity and pharmacological actions of carbon monoxide-releasing molecules. Curr Pharm Des. 2003;9: 2525-2539.
113. Abraham NG, Mieyal PA, Quan S, et al. Modulation of cyclic GMP by retrovirus-mediated human heme oxgyenase-1 gene transfer in microvessel endothelial cells. Am J Physiol. 2002;283:L1117-L1124.
114. da Silva JL, Morishita T, Escalante B, et al. Dual role of heme oxygenase in epithelial cell injury: contrasting effects of short-term and long-term exposure to oxidant stress. J Lab Clin Med. 1996;128:290 -296.
115. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999;340: 115-126.
116. Agarwal A, Balla J, Balla G, et al. Renal tubular epithelial cells mimic endothelial cells upon exposure to oxidized LDL. Am J Physiol. 1996;271: F814-F823.
117. Yamaguchi M, Sato H, Bannai S. Induction of stress proteins in mouse peritoneal macrophages by oxidized low-density lipoprotein. Biochem Biophys Res Commun. 1993;193:1198 -1201.
118. Agarwal A, Shiraishi F, Visner GA, et al. Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells. J Am Soc Nephrol. 1998;9:1990-1997.
119. Ishikawa K, Sugawara D, Wang X, et al. Heme oxygenase-1 inhibits atherosclerotic lesion formation in ldl-receptor knockout mice. Circ Res. 2001;88:506 -512.
120. Ishikawa K, Sugawara D, Goto J, et al. Heme oxygenase-1 inhibits atherogenesis in Watanabe heritable hyperlipidemic rabbits. Circulation. 2001; 104:1831-1836.
121. Yet SF, Layne MD, Liu X, et al. Absence of heme oxygenase-1 exacerbates atherosclerotic lesion formation and vascular remodeling. FASEB J. 2003; 17:1759 -1761.
122. Li M, Peterson S, Husney D, et al. Interdiction of the diabetic state in NOD mice by sustained induction of heme oxygenase: possible role of carbon monoxide and bilirubin. Antioxid Redox Signal. 2007;9:855- 863.
123. Gao X, Belmadani S, Picchi A, et al. Tumor necrosis factor-alpha induces endothelial dysfunction in Lepr(db) mice. Circulation. 2007; 115:245-254.
124. Korobowicz A. Biology of tumor necrosis factor type alpha (TNF-alpha) [in Polish]. Pol Merkur Lekarski. 2006;21:358 -361.
125. Chen J, Liu Y, Liu H, et al. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis. Biochem J. 2006;393:255-265.
126. Hadi HA, Carr CS, Al SJ. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1:183-198.
127. Kawamura K, Ishikawa K, Wada Y, et al. Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol. 2005;5:155-160.
128. Kruger AL, Peterson S, Turkseven S, et al. D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes. Circulation. 2005;111:3126 -3134.
129. Peterson SJ, Husney D, Kruger AL, et al. Long-term treatment with the apolipoprotein A1 mimetic peptide increases antioxidants and vascular repair in type I diabetic rats. J Pharmacol Exp Ther. 2007;322:514 -520.
130. Nakayama M, Takahashi K, Komaru T, et al. Increased expression of heme oxygenase-1 and bilirubin accumulation in foam cells of rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2001;21:1373-1377.
131. Dulak J, Loboda A, Zagorska A, et al. Complex role of heme oxygenase-1 in angiogenesis. Antioxid Redox Signal. 2004;6:858-866.
132. Bussolati B, Mason JC. Dual role of VEGF-induced heme-oxygenase-1 in angiogenesis. Antioxid Redox Signal. 2006;8:1153-1163.
133. Suzuki M, Iso-o N, Takeshita S, et al. Facilitated angiogenesis induced by heme oxygenase-1 gene transfer in a rat model of hindlimb ischemia. Biochem Biophys Res Commun. 2003;302:138 -143.
134. Alvaro-Gonzalez LC, Freijo-Guerrero MM, Sadaba-Garay F. Inflammatory mechanisms, arteriosclerosis and ischemic stroke: clinical data and perspectives [in Spanish]. Rev Neurol. 2002;35:452- 462.
135. Ameriso SF, Villamil AR, Zedda C, et al. Heme oxygenase-1 is expressed in carotid atherosclerotic plaques infected by Helicobacter pylori and is more prevalent in asymptomatic subjects. Stroke. 2005;36:1896 -1900.
136. Otterbein LE, Bach FH, Alam J, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen- activated protein kinase pathway. Nat Med. 2000;6:422- 428.
137. Zhan Y, Kim S, Izumi Y, et al. Role of JNK, p38, and ERK in platelet-derived growth factor-induced vascular proliferation, migration, and gene expression. Arterioscler Thromb Vasc Biol. 2003;23:795- 801.
138. Sawle P, Foresti R, Mann BE, et al. Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br J Pharmacol. 2005;145:800 - 810.
139. Morita T, Kourembanas S. Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. J Clin Invest. 1995;96:2676 -2682.
140. Morita T, Mitsialis SA, Hoike H, et al. Carbon monoxide controls the proliferation of hypoxic smooth muscle cells. J Biol Chem. 1997;272: 32804-32809.
141. Duckers HJ, Boehm M, True AL, et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med. 2001;7:693- 698.
142. Tulis DA, Keswani AN, Peyton KJ, et al. Local administration of carbon monoxide inhibits neointima formation in balloon injured rat carotid arteries. Cell Mol Biol (Noisy-le-grand). 2005;51:441- 446.
143. Taille C, El-Benna J, Lanone S, et al. Mitochondrial respiratory chain and NAD(P)H oxidase are targets for the antiproliferative effect of carbon monoxide in human airway smooth muscle. J Biol Chem. 2005;280:25350- 25360.
144. Aizawa T, Ishizaka N, Taguchi J, et al. Balloon injury does not induce heme oxygenase-1 expression, but administration of hemin inhibits neointimal formation in balloon-injured rat carotid artery. Biochem Biophys Res Commun. 1999;261:302-307.
145. Tulis DA, Durante W, Peyton KJ, et al. Heme oxygenase-1 attenuates vascular remodeling following balloon injury in rat carotid arteries. Atherosclerosis. 2001;155:113-122.
146. Azevedo LC, Pedro MA, Souza LC, et al. Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis. Cardiovasc Res. 2000;47:436-445.
147. Ollinger R, Bilban M, Erat A, et al. Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation. Circulation. 2005;112:1030 -1039.
148. Braun-Dullaeus RC, Mann MJ, Dzau VJ. Cell cycle progression: new therapeutic target for vascular proliferative disease. Circulation. 1998;98: 82-89.
149. Zhao M, Liu Y, Bao M, et al. Vascular smooth muscle cell proliferation requires both p38 and BMK1 MAP kinases. Arch Biochem Biophys. 2002; 400:199 -207.
150. Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37:517-554.
151. Lozonschi L, Sunamura M, Kobari M, et al. Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models. Cancer Res. 1999;59:1252-1258.
152. Furchgott RF, Jothianandan D. Endothelium-dependent and -independent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels. 1991;28:52- 61.
153. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev. 2006;86:583- 650.
154. Motterlini R, Gonzales A, Foresti R, et al. Heme oxygenase-1 derived carbon monoxide contributes to the suppression of acute hypertensive responses in vivo. Circ Res. 1998;83:568 -577.
155. Quan S, Feldman E, Yang L, et al. Distinct effect of retroviral-mediated IFN-alpha gene transfer on human erythroleukemic and CD34+ cell growth and differentiation. J Hematother Stem Cell Res. 1999;8:491-502.
156. a channels by carbon monoxide in vascular smooth muscle cells. J Biol Chem. 1997;272:8222-8226.
157. Amersi F, Shen XD, Anselmo D, et al. Ex vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38 MAP kinase pathway. Hepatology. 2002;35:815- 823.
158. Brouard S, Berberat PO, Tobiasch E, et al. Heme oxygenase-1-derived carbon monoxide requires the activation of transcription factor NF-kappa B to protect endothelial cells from tumor necrosis factor-alpha-mediated apoptosis. J Biol Chem. 2002;277:17950 -17961.
159. L'Abbate A, Neglia D, Vecoli C, et al. Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats. Am J Physiol Heart Circ Physiol. 2007;293:H3532-H3541.
160. Hangaishi M, Ishizaka N, Aizawa T, et al. Induction of heme oxygenase-1 can act protectively against cardiac ischemia/reperfusion in vivo. Biochem Biophys Res Commun. 2000;279:582-588.
161. Masini E, Vannacci A, Marzocca C, et al. Heme oxygenase-1 and the ischemia-reperfusion injury in the rat heart. Exp Biol Med (Maywood). 2003;228:546 -549.
162. Vulapalli SR, Chen Z, Chua BH, et al. Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis. Am J Physiol Heart Circ Physiol. 2002;283:H688-H694.
163. Melo LG, Agrawal R, Zhang L, et al. Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene. Circulation. 2002;105:602- 607.
164. Yoshida T, Maulik N, Ho YS, et al. H(mox-1) constitutes an adaptive response to effect antioxidant cardioprotection: a study with transgenic mice heterozygous for targeted disruption of the Heme oxygenase-1 gene. Circulation. 2001;103:1695-1701.
165. Yet SF, Perrella MA, Layne MD, et al. Hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase-1 null mice. J Clin Invest. 1999;103:R23-R29.
166. Liu X, Pachori AS, Ward CA, et al. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function. FASEB J. 2006;20:207-216.
167. Coito AJ, Buelow R, Shen XD, et al. Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury. Transplantation. 2002;74:96 -102.
168. Stec DE. Smart gene therapy for the heart. Hypertension. 2004;43:720 -721.
169. Pachori AS, Melo LG, Hart ML, et al. Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury. Proc Natl Acad Sci USA. 2004;101:12282-12287.
170. Liao TD, Yang XP, Liu YH, et al. Role of inflammation in the development of renal damage and dysfunction in angiotensin II-induced hypertension. Hypertension. 2008;52:256 -263.
171. Letavernier E, Perez J, Bellocq A, et al. Targeting the calpain/calpastatin system as a new strategy to prevent cardiovascular remodeling in angiotensin II-induced hypertension. Circ Res. 2008;102:720 -728.
172. Henke N, Schmidt-Ullrich R, Dechend R, et al. Vascular endothelial cell-specific NF-kappa B suppression attenuates hypertension-induced renal damage. Circ Res. 2007;101:268 -276.
173. Gupta A, Rhodes GJ, Berg DT, et al. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Physiol. 2007;293:F245-F254.
174. Fontana L, Eagon JC, Trujillo ME, et al. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007;56: 1010-1013.
175. Wang ZV, Scherer PE. Adiponectin, cardiovascular function, and hypertension. Hypertension. 2008;51:8 -14.
176. Hopkins TA, Ouchi N, Shibata R, et al. Adiponectin actions in the cardiovascular system. Cardiovasc Res. 2007;74:11-18.
177. Ouchi N, Ohishi M, Kihara S, et al. Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension. 2003;42:231-234.
178. Li M, Kim DH, Tsenovoy PL, et al. Treatment of obese diabetic mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes. 2008;57:1526 -1535.
179. Kim DH, Burgess AP, Li M, et al. Heme oxygenase-mediated increases in adiponectin decrease fat content and inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6 in Zucker rats and reduce adipogenesis in human mesenchymal stem cells. J Pharmacol Exp Ther. 2008;325:833- 840.
180. Peterson SJ, Drummond G, Hyun KD, et al. L-4F treatment reduces adiposity, increases adiponectin levels and improves insulin sensitivity in obese mice. J Lipid Res. 2008;49:1658 -1669.
181. Elbatarny HS, Netherton SJ, Ovens JD, et al. Adiponectin, ghrelin, and leptin differentially influence human platelet and human vascular endothelial cell functions: implication in obesity-associated cardiovascular diseases. Eur J Pharmacol. 2007;558:7-13.
182. Jung TW, Lee JY, Shim WS, et al. Adiponectin protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity. Biochem Pharmacol. 2006;72:616-623.
183. Zou AP, Fleming JT, Falck JR, et al. 20-HETE is an endogenous inhibitor of the large-conductance Ca(2+)-activated K+ channel in renal arterioles. Am J Physiol. 1996;270:R228-R237.
184. Zou AP, Imig JD, Ortiz-de-Montellano PR, et al. Effect of P-450 omegahydroxylase metabolites of arachidonic acid on tubuloglomerular feedback. Am J Physiol. 1994;266:F934 -F941.
185. Zou AP, Ma YH, Sui ZH, et al. Effects of 17-octadecynoic acid, a suicide-substrate inhibitor of cytochrome P450 fatty acid omegahydroxylase, on renal function in rats. J Pharmacol Exp Ther. 1994;268: 474 - 481.
186. da Silva JL, Tiefenthaler M, Park E, et al. Tin-mediated heme oxygenase gene activation and cytochrome P450 arachidonate hydroxylase inhibition in spontaneously hypertensive rats. Am J Med Sci. 1994;307:173-181.
187. Patel JV, Lim HS, Hughes EA, et al. Adiponectin and hypertension: a putative link between adipocyte function and atherosclerotic risk? J Hum Hypertens. 2007;21:1- 4.
188. Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclindependent kinase inhibitors (CKIs). Oncogene. 1995;11:211-219.
189. Chow WS, Cheung BM, Tso AW, et al. Hypoadiponectinemia as a predictor for the development of hypertension: a 5-year prospective study. Hypertension. 2007;49:1455-1461.
190. Han SH, Quon MJ, Kim JA, et al. Adiponectin and cardiovascular disease: response to therapeutic interventions. J Am Coll Cardiol. 2007;49:531-538.
191. Iwashima Y, Katsuya T, Ishikawa K, et al. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension. 2004;43:1318-1323.
192. Li HY, Chiu YF, Hwu CM, et al. The negative correlation between plasma adiponectin and blood pressure depends on obesity: a family-based association study in SAPPHIRe. Am J Hypertens. 2008;21:471- 476.
193. Ouchi N, Kobayashi H, Kihara S, et al. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem. 2004;279:1304 -1309.
194. Tomas E, Tsao TS, Saha AK, et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA. 2002;99:16309 -16313.
195. Lihn AS, Pedersen SB, Lund S, et al. The anti-diabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells. Mol Cell Endocrinol. 2008;292:36-41.
196. Dyck JR, Lopaschuk GD. AMPK alterations in cardiac physiology and pathology: enemy or ally? J Physiol. 2006;574:95-112.
197. Laderoute KR, Amin K, Calaoagan JM, et al. 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol. 2006;26: 5336-5347.
198. Schulz E, Dopheide J, Schuhmacher S, et al. Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction. Circulation. 2008;118:1347-1357.
199. Chen K, Kirber MT, Xiao H, et al. Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol. 2008;181:1129 -1139.
200. Murabito JM, Keyes MJ, Guo CY, et al. Cross-sectional relations of multiple inflammatory biomarkers to peripheral arterial disease: the Framingham Offspring Study. Atherosclerosis. In press.
201. Bandyopadhyay GK, Yu JG, Ofrecio J, et al. Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes. 2006;55:2277-2285.
202. Yang X, Ongusaha PP, Miles PD, et al. Phosphoinositide signaling links O-GlcNAc transferase to insulin resistance. Nature. 2008;451:964 -969.
203. Dimmeler S, Fleming I, Fisslthaler B, et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399:601- 605.
204. Chen ZP, Mitchelhill KI, Michell BJ, et al. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 1999;443:285-289.
205. Wulster-Radcliffe MC, Ajuwon KM, Wang J, et al. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem Biophys Res Commun. 2004;316:924 -929.
206. Rodella L, Lamon BD, Rezzani R, et al. Carbon monoxide and biliverdin prevent endothelial cell sloughing in rats with type I diabetes. Free Radic Biol Med. 2006;40:2198 -2205.
207. Sambuceti G, Morbelli S, Vanella L, et al. Diabetes impairs the vascular recruitment of normal stem cells by oxidant damage; reversed by increases in pAMPK, heme oxygenase-1 and adiponectin. Stem Cells. In press.
208. Grosser N, Abate A, Oberle S, et al. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun. 2003;308:956 -960.
209. Polte T, Oberle S, Schroder H. 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. 1997;29:3305-3310.
210. Grosser N, Hemmerle A, Berndt G, et al. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med. 2004;37:2064 -2071.
211. Grosser N, Erdmann K, Hemmerle A, et al. Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1. Biochem Biophys Res Commun. 2004;325:871- 876.
212. Lee TS, Chang CC, Zhu Y, et al. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation. 2004;110:1296 -1302.
213. Heinecke JW. Lipoprotein oxidation in cardiovascular disease: chief culprit2 or innocent bystander? J Exp Med. 2006;203:813- 816.
214. Wu BJ, Kathir K, Witting PK, et al. Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging. J Exp Med. 2006;203:1117-1127.
215. Ishizaka N, De Leon H, Laursen JB, et al. Angiotensin II-induced hypertension increases heme oxygenase-1 expression in rat aorta. Circulation. 1997;96:1923-1929.
216. Yuan LX, Liu HM, Li M, et al. Effects of Losartan on expression of heme oxygenases in volume-overloaded rats with left-to-right shunt [in Chinese]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005;36:668-671.
217. Izuhara Y, Nangaku M, Inagi R, et al. Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. J Am Soc Nephrol. 2005;16:3631-3641.
218. Das S, Fraga CG, Das DK. Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB. Free Radic Res. 2006;40:1066 -1075.
219. Kaga S, Zhan L, Matsumoto M, et al. Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1, heme oxygenase-1 and vascular endothelial growth factor. J Mol Cell Cardiol. 2005;39:813- 822.
220. Huang HM, Liang YC, Cheng TH, et al. Potential mechanism of blood vessel protection by resveratrol, a component of red wine. Ann NY Acad Sci. 2005;1042:349 -356.
221. Evgenov OV, Pacher P, Schmidt PM, et al. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov. 2006;5:755-768.
222. Van Eickels M, Wassman S, Schäfer A, et al. Role of sGC activator ataciquat sodium (HMR1766) in cardiovascular disease. BMC Pharmacol. 2007;7(suppl 1):S4.
223. Abraham NG, Scapagnini G, Kappas A. Human heme oxygenase: cell cycle-dependent expression and DNA microarray identification of multiple gene responses after transduction of endothelial cells. J Cell Biochem. 2003;90:1098 -1111.