Heme oxygenase-1 (HO-1) is an enzyme found throughout the human body, playing a widespread role in maintaining cellular well-being. It helps cells respond to various stressors, contributing to the body’s natural defense mechanisms and supporting the health of tissues and organs.
The Basics of HO-1
Heme oxygenase-1 (HO-1), also known as HMOX1, is an intracellular enzyme found in tissues like the liver, spleen, and kidneys. It is part of the heat shock protein family (HSP32). HO-1’s primary function is to break down heme, a molecule that can be pro-oxidant.
This enzymatic process converts heme into three main bioactive products: biliverdin, carbon monoxide (CO), and free ferrous iron (Fe²⁺). The reaction requires molecular oxygen and reducing equivalents. This breakdown detoxifies and recycles heme within the cell. Biliverdin is then rapidly converted into bilirubin by biliverdin reductase (BVR).
The Protective Power of HO-1
The products of HO-1 activity contribute to cellular protection through distinct mechanisms. Biliverdin is quickly transformed into bilirubin; both are potent antioxidants. These pigments scavenge reactive oxygen species, reducing oxidative stress that damages cells. High bilirubin concentrations have been linked to enhanced endothelial function and reduced oxidative damage.
Carbon monoxide (CO), a byproduct of heme breakdown, influences various physiological processes. It regulates vascular tone, promoting vasodilation and improving blood flow. CO also exhibits anti-inflammatory and anti-apoptotic effects, modulating immune responses and preventing programmed cell death. It influences mitochondrial function and cellular signal transduction, contributing to its broad cytoprotective actions.
The third product, free ferrous iron, is potentially pro-oxidant if left unbound. HO-1’s activity manages this by stimulating ferritin, a protein that stores iron. This prevents iron from generating harmful free radicals, averting oxidative damage and contributing to anti-inflammatory activities. The combined actions of these byproducts—antioxidant defense from biliverdin/bilirubin, anti-inflammatory and vasodilatory effects from CO, and proper iron regulation—provide comprehensive cellular protection against various forms of stress.
HO-1’s Role in Disease and Recovery
HO-1’s activity has implications across various health and disease states, often acting as an adaptive defense. In cardiovascular diseases like atherosclerosis and myocardial infarction, HO-1 induction protects by reducing inflammation and oxidative stress. Increased HO-1 expression in macrophages improves antioxidant defense and lessens inflammatory components in atherosclerotic lesions. Overexpression of HO-1 in cardiac cells reduces myocardial infarct size and inflammatory cell infiltration following ischemia/reperfusion injury.
In neurodegenerative disorders, HO-1’s role is complex, with both beneficial and potentially detrimental effects. Transient HO-1 induction in injured brain regions may promote neuroprotection and angiogenesis, supporting recovery. However, long-term expression can lead to iron accumulation, potentially contributing to cell death via ferroptosis. The balance of HO-1 expression and its metabolites, like CO and bilirubin, influences neurovascular protection.
HO-1 also plays a role in kidney injury and inflammatory conditions. Its induction improves outcomes in acute kidney injury by alleviating inflammation and oxidative stress. HO-1-expressing macrophages tend towards an M2 phenotype, which upregulates anti-inflammatory cytokines and suppresses pro-inflammatory ones, aiding tissue recovery. Small doses of CO inhalation increase HO-1 levels and reduce renal injury and fibrosis. These findings highlight HO-1’s involvement in tissue repair and recovery, demonstrating its potential as a therapeutic target in inflammatory diseases and organ damage.