Expression pattern of heme oxygenase isoenzymes 1 and 2 in normal and stress-exposed rat liver

Abstract

Heme oxygenase (HO) catalyzes the oxidative cleavage of the ␣-mesocarbon of Fe-protoporphyrin-IX yielding equimolar amounts of biliverdin-IXa, iron, and carbon monoxide. The HO-system consists of two isoenzymes, namely HO-2 and the inducible isoform HO-1, also referred to as heat shock protein (hsp) 32. Although both parenchymal and non-parenchymal liver cells participate in heme metabolism, the expression pattern of the isoenzymes in normal and stress exposed liver is unknown. To study this, rats underwent either endotoxin (lipopolysaccharide [LPS]) challenge, hemorrhagic hypotension, glutathione (GSH) depletion, or cobalt chloride injection, all known to provoke oxidative stress. HO-2 messenger RNA (mRNA) and protein were constitutively expressed in hepatocytes, Kupffer/ endothelial-, and stellate (Ito-) cell enriched fractions. Although both non-parenchymal cell fractions expressed HO-1 transcripts, HO-1 immunoreactive protein was restricted to Kupffer cells in the normal liver. In contrast to HO-2, a significant increase in HO-1 on the whole organ level was noted by hemorrhagic hypotension, GSH depletion, and cobalt chloride injection. However, the distinct stress models led to a strikingly different cell-type specific and sublobular expression pattern of HO-1 gene expression. HO-1 was inducible in sinusoidal lining cells (hemorrhagic hypotension, LPS challenge), in periportal (cobalt chloride), or pericentral (GSH depletion, hemorrhagic hypotension) hepatocytes. The blockade of protein translation before hemorrhage by cycloheximide reduced upregulation of HO-1/hsp32 mRNA significantly (65.4% reduction, P F .05), whereas the inducibility of hsp70 transcript was maintained. In addition to transcriptional regulation, HO-1 seems to be subject to posttranscriptional control in particular in non-parenchymal cells. (HEPATOLOGY 1998;27:829-838.)The removal of both damaged red blood cells and plasma hemoglobin from the circulation can be mainly attributed to the spleen and liver, and to a lesser extent to other phagocytic cells, for instance in the bone marrow. 1 These cells possess high amounts of heme oxygenase (EC 1.14.99.3), a microsomal enzyme which catalyzes the initial and rate limiting reaction in heme catabolism, i.e., the oxidative cleavage of the ␣-mesocarbon bridge of b-type heme molecules to yield equimolar quantities of biliverdin-IXa, carbon monoxide, and iron. 2 Interestingly, other organ systems which are not involved in the removal of senescent red blood cells, such as the central nervous system or the testes, have also been reported to express heme oxygenase activity reflecting a more versatile role of HO as a cellular signaling pathway. 3 In this regard, evidence suggests that carbon monoxide, a long disregarded product of this pathway, may, like nitric oxide acting on soluble guanylyl cyclase, 4,5 increase cyclic 3': 5'guanosinemonophosphate, a second messenger involved in regulation of a multitude of parenchymal and non-parenchymal liver cell functions. HO exists in two isoforms, i.e., HO-1 and...

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

“…HO-1, in contrast to the second isoform HO-2, is inducible by various stimuli. 1,2 To investigate HO effects in vitro as well as in vivo, HO-1 can be induced by application of cobalt-protoporphyrin-IX (CoPP), for example, while tin-protoporphyrin-IX (SnPP) suppresses HO activity. 3,4 In the liver, administration of CoPP to mice results in HO-1 expression in hepatocytes as well as in Kupffer cells.…”

Nitric oxide in liver injury

“…33,34 HO-1, also known as heat shock protein 32, is induced by oxidative stress, heat shock, and other potentially injurious stimuli including NO. 35,36 Carbon monoxide causes vasodilation by activating guanyl cyclase in a manner similar to NO. In certain injuries, such as that accompanying hemorrhagic shock and resuscitation, inhibition of HO-1, but not NOS, impairs sinusoidal perfusion and exacerbates injury.…”

A cytotoxic drug against reperfusion injury?

“…17 A central and ubiquitous role of these stress enzymes has been shown in several models of ischemic preconditioning including the liver. [27][28][29][30] The heme oxygenase system consists of two principal isoforms, the oxidative stress-inducible heme oxygenase 1 (HO-1, HSP32) and the constitutive heme oxygenase-2 (HO-2). 17 HO-2 does not belong to the family of heat-shock proteins.…”

“…17 None of these inducers of HO-1 increase the expression of HO-2. 30 The only known inducers of HO-2 are adrenal glucocorticoids. 17 Under normal physiological conditions HO-2 is the predominant isoform present in the liver, 17,30 and approximately 85% of HO activity is located in hepatocytes.…”

“…30 The only known inducers of HO-2 are adrenal glucocorticoids. 17 Under normal physiological conditions HO-2 is the predominant isoform present in the liver, 17,30 and approximately 85% of HO activity is located in hepatocytes. 30 After a stress event, the protein levels of HO-1 increase up to 30 times the physiologic levels.…”