Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 118 (12), 1940-1959

Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival


Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival

Leo E Otterbein et al. Circ Res.


Understanding the processes governing the ability of the heart to repair and regenerate after injury is crucial for developing translational medical solutions. New avenues of exploration include cardiac cell therapy and cellular reprogramming targeting cell death and regeneration. An attractive possibility is the exploitation of cytoprotective genes that exist solely for self-preservation processes and serve to promote and support cell survival. Although the antioxidant and heat-shock proteins are included in this category, one enzyme that has received a great deal of attention as a master protective sentinel is heme oxygenase-1 (HO-1), the rate-limiting step in the catabolism of heme into the bioactive signaling molecules carbon monoxide, biliverdin, and iron. The remarkable cardioprotective effects ascribed to heme oxygenase-1 are best evidenced by its ability to regulate inflammatory processes, cellular signaling, and mitochondrial function ultimately mitigating myocardial tissue injury and the progression of vascular-proliferative disease. We discuss here new insights into the role of heme oxygenase-1 and heme on cardiovascular health, and importantly, how they might be leveraged to promote heart repair after injury.

Keywords: carbon monoxide; heme oxygenase-1; inflammation; mitochondria; myocardial ischemia.


Figure 1
Figure 1. Schematic representation of the heme oxygenase pathway
Heme, either derived from intracellular sources, such as hemoproteins and mitochondria, or from damaged tissues and red blood cell hemolysis (extracellular sources) is utilized by heme oxygenase enzymes (HO-1 and HO-2) to generate carbon monoxide (CO), biliverdin and iron. Biliverdin is converted to bilirubin by biliverdin reductase (BVR), while iron is stored in the ferritin protein. Although heme oxygenase enzymes were initially localized in the endoplasmic reticulum, recent reports suggest that HO-1 can be found under certain conditions in other cellular compartments such as the nucleus.
Figure 2
Figure 2. Landmarks in the history of heme oxygenase research
This is not an exhaustive list as additional important findings have been published over the years by scientists working in the field and are not reported here due to space limitation.
Figure 3
Figure 3. Interaction of CO with mitochondria
CO at high concentrations is known to inhibit mitochondrial respiration by competing with oxygen for the binding to cytochrome c oxidase (complex IV). In contrast, controlled delivery of CO gas and CO-RMs at non-toxic concentrations can protect cardiac tissue by promoting mitochondrial biogenesis, uncoupling activity and metabolic switch (see text for details). The molecular mechanism(s) underlying these effects remains to be defined. However, the interaction of CO with mitochondrial targets different from cytochrome c oxidase is likely as the electron transport chain contains other heme-complexes that may display distinct sensitivities to CO.
Figure 4
Figure 4. Heme release and cardiac repair
IR injury leads to the sudden release of cellular contents including heme, mitochondrial DNA and ATP. These cellular DAMPs have each been shown to induce HO-1. HO-1 expression and the subsequent generation CO, biliverdin (BV) and bilirubin (BR) target a variety of cell types that impact cellular repair and tissue regeneration.

Similar articles

See all similar articles

Cited by 23 PubMed Central articles

See all "Cited by" articles

Publication types