The Protective Role of Heme Oxygenase-1 in Atherosclerotic Diseases

Abstract

Heme oxygenase-1 (HO-1) is an intracellular enzyme that catalyzes the oxidation of heme to generate ferrous iron, carbon monoxide (CO), and biliverdin, which is subsequently converted to bilirubin. These products have anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-thrombotic properties. Although HO-1 is expressed at low levels in most tissues under basal conditions, it is highly inducible in response to various pathophysiological stresses/stimuli. HO-1 induction is thus thought to be an adaptive defense system that functions to protect cells and tissues against injury in many disease settings. In atherosclerosis, HO-1 may play a protective role against the progression of atherosclerosis, mainly due to the degradation of pro-oxidant heme, the generation of anti-oxidants biliverdin and bilirubin and the production of vasodilator CO. In animal models, a lack of HO-1 was shown to accelerate atherosclerosis, whereas HO-1 induction reduced atherosclerosis. It was also reported that HO-1 induction improved the cardiac function and postinfarction survival in animal models of heart failure or myocardial infarction. Recently, we and others examined blood HO-1 levels in patients with atherosclerotic diseases, e.g., coronary artery disease (CAD) and peripheral artery disease (PAD). Taken together, these findings to date support the notion that HO-1 plays a protective role against the progression of atherosclerotic diseases. This review summarizes the roles of HO-1 in atherosclerosis and focuses on the clinical studies that examined the relationships between HO-1 levels and atherosclerotic diseases.

Heme Oxygenase Dependent Bilirubin Generation in Vascular Cells: A Role in Preventing Endothelial Dysfunction in Local Tissue Microenvironment?

“…Heme degradation occurs in all cell types in order to complete the turnover of heme-containing proteins. Furthermore, HMOX1 induction crucially drives cell adaptive responses to stressors and its metabolic products exert potent biological activities (Siow et al, 1999;Otterbein et al, 2016;Kishimoto et al, 2019). CO has anti-apoptotic and antiinflammatory activities (Ryter et al, 2002), both intracellularly and in the microenvironment (Morita and Kourembanas, 1995) of blood vessels by increasing cGMP concentration and activating the MAPK pathway (Siow et al, 1999;Ryter et al, 2002).…”

The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis—Therapeutic Opportunities in Hemolytic Conditions

“…Therefore, there is an urgent need for new treatment strategies. HO-1 has been suggested as a potential therapeutic target (reviewed in [ 137 ]). HO-1 binds and degrades heme intracellularly, and the resulting degradation product bilirubin has antioxidant effects [ 138 ].…”

Human Heme Oxygenase-1 Induced by Interleukin-6 via JAK/STAT3 Pathways Is a Tumor Suppressor Gene in Hepatoma Cells

“…In general, the level of HO-1 expression is low when cells are at the resting stage, but profoundly enhanced by certain conditions or stimulators, such as heavy metals, heme, cytokines, hormones, lipid metabolites, and oxygen status [2]. In addition, recent studies have shown that HO-1 is involved in the improvements of several events, such oxidation stress, airway inflammation, functions of adipocytes, obesity, steatohepatitis, atherosclerosis, diabetes mellitus, brain hemorrhage, as well as neuroprotection [3][4][5][6][7][8]. This is especially essential in the health maintenance of the liver which contains about 15% of body heme [9][10][11][12].…”

“…This is especially essential in the health maintenance of the liver which contains about 15% of body heme [9][10][11][12]. Numerous studies have proved that the anti-inflammatory, antioxidant, pro-angiogenic, anti-thrombotic, and anti-apoptotic effects of HO-1 are derived from its catabolic byproducts, CO and biliverdin, which render HO-1 as a tissue protector and a good candidate for investigating new therapeutic interventions [1,8,13]. However, several studies have extensively demonstrated the positive role of HO-1 in cancer progress [14][15][16].…”