Given the major differences between the

Given the major differences between the molecular regulation of the genes encoding HO-1 (HMOX1) in mice and humans, it is not appropriate to utilize mouse models for mechanistic analyses of human HMOX1[35]. In addition, it has been reported that drugs, such as statins, as well as stressors and the redox microenvironment, are able to regulate HO-1 expression. Currently, the HO-1 system is being explored for use in regenerative medicine and has been implicated in neovascularization processes [36]. Neovascularization is crucial for physiological processes such as tissue development and regeneration. Enhanced HO-1 expression or the pharmacological application of HO end products is associated with protection in preclinical models of tissue injury, in particular those leading to angiogenesis [37]. In this context, HO-1 has been shown to stimulate 11e receptor progression and proliferation in vascular endothelium. Although the mechanism by which HO-1 is able to stimulate the growth of vascular endothelium is not known, the ability of HO-1 to stimulate the synthesis of vascular endothelial growth factor (VEGF) from vascular cells may contribute to its proliferative action [38]. During chronic inflammation, HO-1 may inhibit leukocyte infiltration and facilitates tissue repair by promoting VEGF-driven noninflammatory angiogenesis. Angiogenesis was shown to be impaired in diabetic mouse models of hind-limb ischemia and wound healing, owing to decreased expression of VEGF [39].
Targeting Biliverdin Reductase as Therapy for Inflammation and Diabetes As discussed above, biliverdin is formed in a single reaction during the catalysis of HO-1 and HO-2, with CO and iron also being released simultaneously. The conversion of biliverdin to BR is catalyzed by BVR-A using NADH and NADPH as the electron donors (Box 2). Usually known for its toxicity but now recognized as a potent protective molecule, BR is receiving increased attention because of its biomolecular effects. It has regulatory functions in several biological processes via the activity of BVR. Multiple cellular and molecular cascades are likely to underlie BR-induced neuronal injury, including excitotoxicity, neuroinflammation, and cell cycle arrest. Disorders of BR binding to albumin may be associated with clinical signs of neurological injury [47], and BR-induced neurotoxicity in preterm neonates is an ongoing clinical concern. In humans, unconjugated BR (UCB) is one of the most-potent endogenous antioxidants, while, similar to uric acid, BR is one of the most-active antioxidant molecules. However, hyperbilirubinemia has long been recognized as a marker of liver dysfunction. It is anticipated that each cell and/or tissue may have different thresholds of intracellular UCB levels that result in either protective or deleterious outcomes [40]. In humans, a low (<7mmol/l) total BR concentration is a known risk factor for diseases associated with increased OS, such as cardiovascular diseases and diabetes 48, 49 (Box 3).
Targeting HO-1 Activation as a Therapy for Inflammation and Diabetes
Concluding Remarks and Future Perspectives Manipulation of the Nrf2/HO-1 pathway protects against a variety of conditions characterized by oxidative damage and inflammation. Potent activators of the Nrf2/HO-1 pathway [i.e., carnosol, cobalt protoporphyrin (CoPP), and dimethyl fumarate] were shown to modulate inflammation in mouse microglial cells [68]. Metalloporphyrins, particularly CoPP can increase the expression of HO-1. CoPP also affects the expression of antioxidant genes and recent data indicate that it reduces mitochondrial production mediated by Foxo1 [69]. To treat diabetes-induced endothelial dysfunction, the development of new inhibitors of the major ROS-producing systems in relation to HO-1 expression could be an alternative to conventional antioxidant therapies [12]. One of the main research challenges has been to find ways to attenuate OS to improve the symptoms of diabetes. However, the lack of evidence of the beneficial effects of antioxidant vitamins in the prevention of OS-related pathologies has forced the development of new strategies. As a gene therapy target, HO is particularly well suited for therapeutic interventions in terms of immunity or cardiometabolic health. Recent results suggest that the HO-1/CO system can prevent and reduce the outcome of inflammatory pathologies related to innate and adaptive immunity. Monocytes from patients with systemic lupus erythematosus, which manifests as exacerbated general inflammation, showed a reduced expression of HO-1 [70]. Observations were consistent with data showing that mitochondria have a key role in the initiation of the innate immune response. In this field, recent concepts could contribute to the design of new therapeutic tools for inflammation-based diseases. The exploitation of the molecular targets of the HO-1/CO system, such as mitochondria, is as a promising alternative for the creation of anti-inflammatory therapies [71]. Over the past few years, gene transfers have become the most promising emerging therapy. The successful transfer of HMOX1 to target sites can have beneficial effects in various diseases. For example, diabetic mice treated with adenoviral vectors containing HO-1 showed increases in wound healing and neovascularization [72]. Direct delivery of HO-1 using recombinant adeno-associated virus as a vector prevented ischemia-induced myocardial infarction injury as well as heart allograft deterioration [73]. Thus, despite its existing limitations and questions over its use, gene therapy for cardiovascular and metabolic diseases shows great potential.