Heme oxygenase-1 (HO-1) degrades heme into carbon monoxide (CO), iron, and biliverdin and is ubiquitously distributed in mammalian tissues. HO-1 is strongly and rapidly induced by a variety of stimuli and agents that cause oxidative stress under pathological conditions. Increased HO-1 expression has been proposed to reduce inducible nitric oxide synthase (iNOS) activity through accelerated degradation of heme thereby exerting a protective effect in animal models of inflammation.

Oxidative stress also stimulates compensatory angiogenesis. Angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Both stimulators and inhibitors of angiogenesis are being developed. Inhibitors are being developed for the treatment of cancer and more recently for the treatment of rheumatoid arthritis. On the other hand, stimulators of angiogenesis are being developed for the treatment of ischemic diseases such as stroke, myocardial infarction and peripheral artery occlusive disease (PAOD; PVD). PAOD is a common condition with variable morbidity affecting mostly men and women older than 50 years. Based on incidence rates extrapolated to today's increasingly aging population, PAOD affects as many as 10 million people in the United States including 5% of people aged 50 or over. As the population ages, the family physician will be faced with increasing numbers of patients complaining of symptoms of lower extremity PAOD. Nearly 25% of patients remain undiagnosed until a major limb-threatening occlusion occurs. The condition can be seriously debilitating, and in the most severe cases PAOD can cause limb-threatening ischemia. Interventions include vascular surgery or bypass surgery and thrombolysis by catheter-directed intra-arterial thrombolytics. Since the first-line thrombolytic has recently been withdrawn from the market, new pharmacologic options are urgently required.

Since oxidative stress stimulates HO-1 expression and angiogenesis it is possible that HO-1 may directly stimulate angiogenesis. This is supported by in vitro data since gene transfer of human HO-1 into coronary endothelial cells has previously been report to confer an angiogenic phenotype on these cells. More recently researchers from the University of Tokyo Graduate School of Medicine have investigated whether HO-1 can induce angiogenic effects in vivo. Rats were subjected to a bolus injection of either wild type adenovirus (ad-wt) or adenovirus encoding HO-1 (ad-HO-1) through the right femoral artery. HO-1 gene transfer resulted in about a six-fold increase in HO-1 protein levels and an increase in both blood flow and capillary density in ischemic hindlimbs. These angiogenic effects of ad-HO-1 infection could be completely abolished by treating the animals with the HO inhibitor, zinc protoporphyrin, indicating that they were specifically due to the expression of HO-1.

These data suggest that HO-1 gene transfer can both limit inflammatory damage and promote blood flow in ischemic hindlimb supporting the use of such gene therapies or alternatively small molecules that stimulate HO-1 in the treatment of patients with ischemic disease. Both of these therapeutic strategies are currently under-exploited and therefore represent a novel area of drug discovery. Earlier studies have reported that HO-1 protects against vascular constriction and such treatments may therefore be of benefit both as acute and chronic treatments of ischemia.

Entry date Friday, April 11, 2003

Adapted from Suzuki et al, Biochem Biophys Res Commun 2003 Feb 28;302(1):138-43 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk