© 2001 American Heart Association, Inc.
Editorial |
Oxidative Stress and Apoptosis in Heart Failure Progression
From the Department of Medicine, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to Joshua M. Hare, MD, Johns Hopkins Hospital, Division of Cardiology, 600 N Wolfe St, Carnegie 568, Baltimore, MD 21287-6568. E-mail jhare@mail.jhmi.edu
Key Words: mitochondria • xanthine oxidase • cytochrome c • superoxide • nitric oxide
The syndrome of congestive heart failure (HF) is the most important cardiovascular disorder in the Western world from public health and health care resource utilization perspectives.1 Great strides have been made in treating patients with HF through the development of drugs that antagonize neurohormonal activation.2 Nevertheless, patients with HF experience clinically meaningful disease progression despite optimal current therapy.
Although the biological mechanisms for progression and ventricular remodeling have yet to be definitively explained, mounting evidence supports the theory that ventricular dysfunction worsens as a consequence of increased reactive oxygen species (ROS) formation, which in turn promotes myocyte apoptosis.3 Myocyte apoptosis is observed in numerous pathological situations including cardiomyopathy,4 ischemia,5 and transplant rejection6 and can be induced experimentally with neurohormonal agonists7 or direct generation of superoxide.8
In this issue of Circulation Research, Cesselli et al9 have examined the linkage between pathways involved in mediating oxidative metabolism and apoptosis in dogs with pacing-induced dilated cardiomyopathy. Using both immunohistochemistry and immunoblotting techniques, the authors track changes in multiple apoptotic pathways including the caspases, mitochondrial cytochrome c release, and proteins involved in DNA damage (see Figure). Importantly, induction of these changes precedes the development of left ventricular (LV) dysfunction, providing additional strong support, but not definitive proof, that apoptosis participates in the progression of LV remodeling. In addition, a new signaling molecule, p66shc, linking oxidative stress and apoptosis is demonstrated to be upregulated with pacing-induced HF.10 p66shc is an oxidant stress–induced, proapoptotic proto-oncogene known to be activated by phosphorylation in response
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