Role of oxidative stress in myocardial hypertrophy and failure

Experimental evidence in animal models of myocardial remodeling and failure demonstrate that the failing heart is subjected to increased oxidative stress. The details as to the source of increased ROS production remain to be elucidated, but a likely contributor appears to be increased production of ROS by mitochondria, possibly due to impaired coupling of the oxidative phosphorylation. An NAD(P)H oxidase appears to exist in the myocardium and may contribute to changes in myocyte growth and gene expression as a source of signaling levels of ROS. Maladaptive changes in antioxidant enzyme activity may also contribute to the oxidative stress of the failing heart. At a cellular level, oxidative stress can induce most, if not all, of the changes that are thought to contribute to myocardial remodeling - myocyte hypertrophy, apoptosis, fetal gene expression and increased matrix metalloproteinase activity. For cardiac myocytes, the intracellular mechanism that distinguishes the hypertrophic response elicited by low levels of ROS from the apoptotic response elicited by higher levels remains to be defined, but probably involves differences in the type, quantity and/or duration of ROS production. ROS regulate intracellular responses, at least in part, through the activation of intracellular signaling pathways in the stress-activated protein kinase family. In the case of myocyte hypertrophy, ROS appear to act through specific signaling pathways such as the ras-raf-MEK-ERK cascade. While both hypertrophy and apoptosis might be viewed as "stress-responses" in the failing heart, ROS-dependent activation of hypertrophy may occur in the absence of overt oxidative "stress" (i.e. oxidative damage to intracellular proteins, lipids, and nucleic acids). In contrast, myocyte death by apoptosis or necrosis in the setting of higher levels of ROS is more likely to be a response to overt oxidative "stress". In the latter case, there is early activation of multiple stress-activated pathways, the role of which remains to be defined. Many events in myocardial remodeling are regulated by extracellular stimuli such as mechanical strain, neurohormones or cytokines. These stimuli cause the activation of one or more intracellular signaling pathways which mediate changes in the phenotype of cardiac myocytes and fibroblasts. The importance of this latter concept has been emphasized by the ability of drugs that interrupt these compensatory systems (e.g. vasodilators, angiotensin converting enzyme inhibitors and β-adrenergic receptor blockers) to slow or even reverse the remodeling process, and thereby to exert important benefits on the clinical course of patients. In this context, it is noteworthy that many of the deleterious cellular phenotypes present in hypertrophied and failing myocardium may be attributed to ROS and oxidative stress. A more detailed understanding of the role of ROS and oxidative stress in myocardial remodeling therefore has the potential to generate novel therapeutic approaches to the prevention and treatment of heart failure.