Haeme oxygenase signalling pathway: implications for cardiovascular disease

Abstract

Evidence now points to the haeme oxygenase (HO) pathway as a possible actor in modulating risk for cardiovascular disease (CVD). In particular, the HO pathway may represent a key endogenous modulator of oxidative, inflammatory, and cytotoxic stress while also exhibiting vasoregulatory properties. In this review, we summarize the accumulating experimental and emerging clinical data indicating how activity of the HO pathway and its products may play a role in mechanisms underlying the development of CVD. We also identify gaps in the literature to date and suggest future directions for investigation. Because HO pathway activity can be influenced not only by genetic traits and environmental stimuli but also by a variety of existing pharmacologic interventions, the pathway could serve as a prime target for reducing the overall burden of CVD. Further work is needed to determine the role of HO pathway products as possible prognostic markers of risk for clinical CVD events and the extent to which therapeutic augmentation or inhibition of HO pathway activity could serve to modify CVD risk.

Keywords: Bilirubin; Biliverdin; Carbon monoxide; Cardiovascular disease; Heme oxygenase pathway.

Figure 1

Overview of haeme metabolism and the central role of haeme-oxygenase activity.

Figure 2

Several stimuli have been shown to induce HO-1 activity and, in turn, upregulated HO-1 expression may provide cardiovascular protection.

Figure 3

Certain transcription factors, Nrf2 and Bach1, appear to play an important role in regulating HO-1 expression in cardiovascular conditions. Specifically, Nrf2 and Bach1 form heterodimers with Maf proteins and bind to consensus antioxidant response element (ARE) sequences in the HO-1 promoter. Nrf2 transactivates the HO-1 promoter and may provide protection against diabetes and cardiovascular disease. Bach-1 competes with Nrf2/Maf dimers and represses HO-1 transcription. Accordingly, deficiency of Bach1 has been shown to be protective in animal models of atherosclerosis, myocardial ischaemia-reperfusion injury, and vascular injury.

Figure 4

Schematic displaying the possible relationship between HO activity and cardiometabolic stressors, where maintenance of physiologic balance (A) involves HO pathway products countering stressors that activate HO activity (B).