New Biotechnological Methods to Reduce Oxidative Stress in the Cardiovascular System: Focusing on the Bach1/Heme Oxygenase-1 Pathway

Oxidative stress is involved in the mechanism of atherosclerotic lesion formation and in the mechanisms underlying the development of other pathogenic conditions of the cardiovascular system, including endothelial dysfunction, hypertension, and heart failure. Reducing oxidative stress may be a reasonable therapeutic approach to treat cardiovascular diseases. HO-1 is a cytoprotective enzyme that is induced in response to oxidative stress and degrades heme into carbon monoxide (CO) and bilirubin, both of which have cytoprotective effects. A substantial body of evidence suggests that introduction of HO-1, either pharmacologically or by a gene delivery technique, confers cytoprotection in ischemic heart disease and atherosclerosis in animals. Recent studies have revealed that CO has anti-inflammatory properties and that administration of CO provides protection against atherosclerosis and ischemic heart disease. Discovery of Bach1, a transcriptional repressor of HO-1, has greatly contributed to the understanding of the regulation of HO-1 expression, providing a clue to a development of alternative method to enhance HO activity. Bach1 normally represses HO-1 expression. However, upon exposure to oxidative stress, Bach1 loses its repressive activity and is exported out of the nucleus, which in turn results in the upregulation of HO-1. Bach1 knockout mice, expressing an increased amount of HO-1, are resistant to pro-atherosclerotic and ischemic stresses. These findings indicate that inhibition of Bach1 may be a novel approach to enhance protection against stress. In summary, the Bach1-HO-1 system is an important defense mechanism against oxidative stress. Development of a safe and effective method to enhance this pathway, such as Bach1 inhibitor, may be of great clinical relevance.