Reactive oxygen species signaling in cardiac remodeling and failure

Abstract

Despite major advances in treatment, chronic heart failure (CHF) remains one of the leading causes of mortality and morbidity in the western world. Although the stimuli for CHF are wide ranging, the underlying pathophysiological response, known as cardiac remodeling, is broadly similar. The process of cardiac remodeling is characterized by a series of initially adaptive structural and functional alterations which become progressively maladaptive and ultimately lead to CHF. Oxidative stress and reactive oxygen species (ROS) play a well-established role in the development and progression of cardiac remodeling. ROS include both free radicals (e.g., superoxide, hydroxyl) and oxidants (e.g., peroxynitrite, hydrogen peroxide) and exert important physiological actions, in addition to their well-documented harmful effects. Increased ROS production has been widely reported in experimental and clinical CHF and has been linked to several key remodeling processes such as cardiomyocyte hypertrophy, apoptosis, contractile dysfunction, and extracellular matrix remodeling. It is now apparent that myocardial ROS function as key regulators of intracellular signaling that are capable of altering the activity of numerous molecules and pathways to exert subtle modulatory effects on cardiac remodeling. Indeed, several key signaling pathways involved in CHF pathogenesis, including MAPKs, Akt, NF-kB, and AP-1 are known to be redox sensitive, with varying thresholds for activation. The downstream effects of ROS appear to be critically dependent upon a number of factors including the source of ROS, cellular localization, temporal regulation, and stimulus for production, which dictate the highly specific and targeted phenotypic changes associated with cardiac remodeling. Although the precise mechanisms underlying ROS-dependent modulation of myocardial signaling remain unknown, it is plainly evident that a more complete delineation of these pathways in cardiac remodeling and CHF holds clear potential for the identification of improved therapeutic targets.