HO-1 overexpression and underexpression: Clinical implications.

In this review we examine the effects of both over- and under-production of heme oxygenase-1 (HO-1) and HO activity on a broad spectrum of biological systems and on vascular disease. In a few instances e.g., neonatal jaundice, overproduction of HO-1 and increased HO activity results in elevated levels of bilirubin requiring clinical intervention with inhibitors of HO activity. In contrast HO-1 levels and HO activity are low in obesity and the HO system responds to mitigate the deleterious effects of oxidative stress through increased levels of bilirubin (anti-inflammatory) and CO (anti-apoptotic) and decreased levels of heme (pro-oxidant). Site specific HO-1 overexpression diminishes adipocyte terminal differentiation and lipid accumulation of obesity mediated release of inflammatory molecules. A series of diverse strategies have been implemented that focus on increasing HO-1 and HO activity that are central to reversing the clinical complications associated with diseases including, obesity, metabolic syndrome and vascular disease.

Translational Significance of Heme Oxygenase in Obesity and Metabolic Syndrome.

The global epidemic of obesity continues unabated with sequelae of diabetes and metabolic syndrome. This review reflects the dramatic increase in research on the role of increased expression of heme oxygenase (HO)-1/HO-2, biliverdin reductase, and HO activity on vascular disease. The HO system engages with other systems to mitigate the deleterious effects of oxidative stress in obesity and cardiovascular disease (CVD). Recent reports indicate that HO-1/HO-2 protein expression and HO activity have several important roles in hemostasis and reactive oxygen species (ROS)-dependent perturbations associated with metabolic syndrome. HO-1 protects tissue during inflammatory stress in obesity through the degradation of pro-oxidant heme and the production of carbon monoxide (CO) and bilirubin, both of which have anti-inflammatory and anti-apoptotic properties. By contrast, repression of HO-1 is associated with increases of cellular heme and inflammatory conditions including hypertension, stroke, and atherosclerosis. HO-1 is a major focus in the development of potential therapeutic strategies to reverse the clinical complications of obesity and metabolic syndrome.

Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats.

Transient reduction in coronary perfusion pressure in the isolated mouse heart increases microvascular resistance (paradoxical vasoconstriction) by an endothelium-mediated mechanism. To assess the presence and extent of paradoxical vasoconstriction in hearts from normal and diabetic rats and to determine whether increased heme oxygenase (HO)-1 expression and HO activity, using cobalt protoporphyrin (CoPP), attenuates coronary microvascular response, male Wistar rats were rendered diabetic with nicotinamide/streptozotocin for 2 wk and either CoPP or vehicle was administered by intraperitoneal injection weekly for 3 wk (0.5 mg/100 g body wt). The isolated beating nonworking heart was submitted to transient low perfusion pressure (20 mmHg), and coronary resistance (CR) was measured. During low perfusion pressure, CR increased and was associated with increased lactate release. In diabetic rats, CR was higher, HO-1 expression and endothelial nitric oxide synthase were downregulated, and inducible nitric oxide synthase and O(2)(-) were upregulated. After 3 wk of CoPP treatment, HO activity was significantly increased in the heart. Upregulation of HO-1 expression and HO activity by CoPP resulted in the abolition of paradoxical vasoconstriction and a reduction in oxidative ischemic damage. In addition, there was a marked increase in serum adiponectin. Elevated HO-1 expression was associated with increased expression of cardiac endothelial nitric oxide synthase, B-cell leukemia/lymphoma extra long, and phospho activator protein kinase levels and decreased levels of inducible nitric oxide synthase and malondialdehyde. These results suggest a critical role for HO-1 in microvascular tone control and myocardial protection during ischemia in both normal and mildly diabetic rats through the modulation of constitutive and inducible nitric oxide synthase expression and activity, and an increase in serum adiponectin.

Chemoprevention of severe neonatal hyperbilirubinemia.

The uses of synthetic heme analogues that are competitive inhibitors of heme oxygenase, the rate-limiting enzyme in the production of bilirubin, represent a novel means of controlling severe hyperbilirubinemia in the newborn. The logic of this approach and the use of stannsoporfin (tin mesoporphyrin) as the compound of choice are discussed.