Haem oxygenases play a pivotal role in placental physiology and pathology

Abstract

Background: Haem oxygenases (HO) catabolise haem, which is the prosthetic group of numerous haemoproteins. Thus, multiple primary cellular pathways and functions rely on haem availability. HO exists in two isoforms, both expressed in the placenta, namely HO-1 and HO-2, the first being inducible. Haem oxygenases, particularly HO-1, have garnered specific interest in the field of physiological and pathological placental function. These enzymes mediate haem degradation by cleaving the alpha methene bridge to produce biliverdin, which is subsequently converted to bilirubin, carbon monoxide and iron. HO-1 has anti-inflammatory and antioxidant activities.

Search methods: An initial literature analysis was performed using PubMed on 3 October 2018 using key terms such as 'haem oxygenase and pregnancy', 'haem oxygenase and placenta', 'HO-1 and pregnancy', 'HO-1 and placenta', 'HO and placenta', 'HO and pregnancy', 'genetic variant and HO', 'CO and pregnancy', 'CO and placenta', 'Bilirubin and pregnancy', 'Iron and pregnancy' and 'PPAR and Haem', selecting consensus conferences, recommendations, meta-analyses, practical recommendations and reviews. A second literature analysis was performed, including notable miscarriages, foetal loss and diabetes mellitus, on 20 December 2019. The three authors studied the publications independently to decipher whether they should be included in the manuscript.

Objective and rationale: This review aimed to summarise current pieces of knowledge of haem oxygenase location, function and regulation in the placenta, either in healthy pregnancies or those associated with miscarriages and foetal loss, pre-eclampsia, foetal growth restriction and diabetes mellitus.

Outcomes: HO-1 exerts some protective effects on the placentation, probably by a combination of factors, including its interrelation with the PGC-1α/PPAR pathway and the sFlt1/PlGF balance, and through its primary metabolites, notably carbon monoxide and bilirubin. Its protective role has been highlighted in numerous pregnancy conditions, including pre-eclampsia, foetal growth restriction, gestational diabetes mellitus and miscarriages.

Wider implications: HO-1 is a crucial enzyme in physiological and pathological placentation. This protective enzyme is currently considered a potential therapeutic target in various pregnancy diseases.

Keywords: bilirubin; carbon monoxide; diabetes mellitus; foetal growth restriction; haem; heme; heme oxygenase; iron; pre-eclampsia; pregnancy.