Heme Oxygenase -1

Heme oxygenase (HO)

American Journal of Respiratory Cell and Molecular Biology 2002; 27:8-16
Pharmacol Rev 55:551-571, 2003
 Soluble guanylyl cyclase

Cardiovascualar Research 41:385-394, 1999

Free Radical Biology & Medicine 39 (2005) 1 – 25
 Characteristics of heme oxygenase (HO) isoforms

Inducible form

Constitutive form

Constitutive form

Cardiovascualar Research 41:385-394, 1999

Subcellular localization of heme
metabolic enzymes

Physiol Rev 86: 583–650, 2006

Respir Res. 2003; 4 (1): 7
Physiol Rev 86: 583–650, 2006
J. Cell. Physiol. 2003Vol.195, 3 Pages: 373-382
Morita et al., Proc. Natl. Acad. Sci. USA 92:1475-1479, 1995.

H H H H

Primary cultures of rat aortic

smooth muscle cells
Pharmacol Rev 55:551-571, 2003
Respir Res. 2003; 4 (1): 7
TABLE 2 Selection of different inducers of HO-1 gene expression

Selection of Inducers of HO-1 References

cGMP Immenschuh and Ramadori, 2000

Abraham et al., 1988; Cantoni et
Cytokines
al., 1991
Endotoxin Gemsa et al., 1974
Heat-shock Shibahara et al., 1987
Heavy metals Maines and Kappas, 1974
Heme Tenhunen et al., 1970
Hydrogen peroxide Keyse and Tyrrell, 1989
Hyperoxia Lee et al., 1996a
Hypoxia Jordi-Racine et al., 1988
Nitric oxide/peroxynitrite Willis et al., 1995
Phorbol esters Abraham et al., 1988
Prostaglandins Koizumi et al., 1992
Shear stress Wagner et al., 1997
Sodium arsenite Sardana et al., 1981
Thiol scavengers (GSH
Yoshida et al., 1987
depletion)
Ultraviolet A Keyse and Tyrrell, 1989

GSH, glutathione. Pharmacol Rev 55:551-571,2003

TABLE 3 Selection of diseases/conditions associated with HO-1
expression

Selection of Pathological Conditions

Associated with HO-1 Expression References

Acquired immunodeficiency
Levere et al., 1993
syndrome
Acute pancreatitis Fu et al., 1997
Acute renal failure Nath et al., 1992
Alzheimer disease Smith et al., 1994
Angiogenesis Deramaudt et al., 1998
Asthma Horvath et al., 1998
Atherosclerosis Siow et al., 1999
Maines and Abrahamsson,
Cancer
1996
Cerebrovascular accident Panahian et al., 1999
Chronic obstructive lung disease Maestrelli et al., 2001
Laniado-Schwartzman et
Corneal inflammation
al., 1997
Diabetes Cosso et al., 2001
Gastrointestinal disease Guo et al., 2001
Hyperoxia-induced lung injury Lee et al., 1996b
Hypertension Johnson et al., 1995
Hypoxic/ischemic injury Bergeron et al., 1997
Iron homeostasis Poss and Tonegawa, 1997a
Ischemia/reperfusion Maines et al., 1993
Nephritis Mosley et al., 1998

Pharmacol Rev 55:551-571,2003

HO and NOS

Basic & Clinical Pharmacology, Katzung, Ch 19, 8th edition, 2001

 NO Regulation of HO Activity

300 µM 25 µM

SNAP: NO donor
SnPP: HO inhibitor

Sheep pulmonary artery endothelial cells

Yee et al., Am. J. Physiol. 271:L512-L518, 1996.

 Foresti et al., J. Biol. Chem. 272:18411-18417, 1997.

Bovine aortic
endothelial cells

SIN-1: NO donors
750 µM

6 hr incubation
 Hartsfield et al., Am. J. Physiol.
271:L980-L988, 1997.

Rat aortic smooth muscle cells AP-1

cGMP analog

SNN: NO donor 500 µM

ODQ: guanylyl cyclase inhibitor

 Willis et al., Biochem. Biophys. Res. Commun. 214:1152-1156, 1995.

Rat brain homogenates

L-NAME L-arginine Na nitroprusside

 HO Regulation of NOS Activity

Rabbit internal anal

sphincter (IAS)

L-NNA: NOS inhibitor

ZnPP: HO inhibitor

Chakder et al., J. Pharmacol. Exp. Ther. 277:1376-1382, 1996.

Hm: HO inducer

ZnPP: HO inhibitor

Turcanu et al., Res. Immunol. 149:741-744, 1998.

 Interaction between NOS and HO

Antioxidants and Redox Signaling 4, 301-307, 2002

Schematic representation of the possible interaction of
HO/CO in the prevention of eNOS uncoupling

Free Radical Biology & Medicine 39 (2005) 1 – 25

Am J Physiol Heart Circ Physiol 281: H981-H986, 2001
The possible role of HO/CO in stenosis and
neointima formation

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Antiatherogenic properties of HO-1

Arterioscler Thromb Vasc Biol. 2005;25:1786-1795

Physiol Rev 86: 583–650, 2006
HO-1
Physiol Rev 86: 583–650, 2006
Physiol Rev 86: 583–650, 2006
Physiol Rev 86: 583–650, 2006
Physiol Rev 86: 583–650, 2006
Physiol Rev 86: 583–650, 2006
Physiol Rev 86: 583–650, 2006
Physiol Rev 86: 583–650, 2006
Signaling pathways leading to ho-1 activation

Physiol Rev 86: 583–650, 2006

Reference
Ryter SW, Alam J, Choi AMK. Heme Oxygenase-
1/Carbon Monoxide: From Basic Science to
Therapeutic Applications. Physiol Rev 86 (2006):
583–650.
Abrahama NG, Kappas A. Heme oxygenase and
the cardiovascular–renal system. Free Radical
Biology & Medicine 39 (2005) 1 – 25.
The end
Basic & Clinical Pharmacology, Katzung, Ch. 19, 8th edition, 2001
Am J Physiol Renal Physiol 285: F178-F190, 2003;
COLEMAN, J. W.
Nitric oxide: a regulator of mast cell activation and mast cell-
mediated inflammation.
Clinical & Experimental Immunology 129 (1), 4-10
COLEMAN, J. W.
Nitric oxide: a regulator of mast cell activation and mast cell-mediated inflammation.
Clinical & Experimental Immunology 129 (1), 4-10
Experimental Biology and Medicine 226:814-824 (2001)
Experimental Biology and Medicine 226:814-824 (2001)
Circulation. 2003;108:1015
Touyz: Curr Opin Nephrol Hypertens, Volume 12(2).March 2003.165-174
TABLE 1 Summary of the various functions of HO isoforms, their
tissue distribution, and gene regulation
Pharmacol Rev 55:551-
571,2003
HO-1 (hsp32) HO-3
Isoform HO-2 Isoform Isoform

Physiological Heme Heme

Heme degradation
roles degradation binding
(Selection of
Anti-oxidant defense Heme binding
functions)
Modulation of
Maintenance of
vascular tone and
vascular tone
liver perfusion
Neural signaling Neural signaling
Anti-inflammatory
actions
Down-modulation of
adhesion molecule
expression
Regulation of
hemo-proteins
activity
Most tissues, e.g.:
brain, retina,
Constitutive
liver, spleen, Most
tissue Spleen Liver
testis, lungs, tissues
expression
kidney,
vasculature
Very diverse, e.g.:
Adrenal
Inducers of oxidative stress, Not
glucocorticoids,
expression cytokines, heavy known
opiates
metals, hypoxia,
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