Heme Oxygenase: Introduction

The heme oxygenases (HOs) are key enzymes in the oxidative degradation of heme to biliverdin (biliverdin IXα), carbon monoxide (CO), and ferrous iron (Fe²⁺) ¹. In mammals, two main isoforms are expressed: HO-1 (also known as Hsp32) and HO-2. While HO-2 is constitutively expressed under basic requirements in the majority of human tissues, HO-1 represents the inducible HO variant whose expression is highly up-regulated upon exposure to different kinds of stress ^2-4. HO-1 and HO-2 have originally been characterized as being associated with membranes of the smooth ER. Intriguing reseach also revealed an association of HO-1 with extra-ER compartments, including the cytosol ^5,6, mitochondria ^7,8, plasma membrane caveolae⁹, chloroplasts ^10-13, extracellular space ¹⁴, and the nucleus ¹⁵. HOs play a crucial role in maintaining redox homeostasis due to their anti-oxidant, anti-inflammatory and anti-apoptotic characteristics. Apart from its enzymatic activity, HO-1 possesses other physiological functions including chaperone activity mediated by protein-protein interactions, transcriptional regulation, intracellular compartmentalization, and immunomodulation ^16,17. Extracellular HO-1 might function as a potential biomarker in disease ^18,19 or as an extracellular receptor ligand²⁰. HO-1 has emerged as a promising therapeutic target in a broad spectrum of human diseases, such as cardiovascular, inflammatory, and neurodegenerative disorders as well as cancer²¹ in which HO-1 levels are usually up-regulated. Patients with up-regulated HO-1 expression frequently show a reduced survival rate and poor clinical outcome²². The definite role of HO-1 in carcinogenesis is controversial and multifaceted. In contrast to its well documented pro-tumorigenic actions, HO-1 has also been found to exert anti-tumorigenic effects in cancer^23-26. Targeting HO-1 aiming at modulating HO-1 expression is being evolved into an excellent therapeutic tool in a conceivably wide spectrum of disorders.