Ceruloplasmin and Heart Failure
Oxidative stress is a major mechanism contributing to heart failure (HF) pathogenesis. On one hand, oxidative reactions are central to a wide range of signaling cascades, both physiological and pathological. Such redox signaling events participate in the governance of myocyte plasticity, ion homeostasis, excitation–contraction coupling, and metabolism. However, high levels of oxidative stress can damage proteins, membranes, and DNA. There is great interest in understanding mechanisms whereby oxidative events contribute to disease pathogenesis, because clinical trials of antioxidant therapies in HF have disappointed.
Article, see p 1723
One mechanism whereby reactive oxygen species contribute to disease pathophysiology is via post-translational modification of specific proteins.1 One such modification is tyrosine nitration. Tyrosine nitration is a covalent coupling of protein tyrosine residues with nitric oxide (•NO)–derived oxidants. Three major sources of •NO-derived reactive species have been identified2: (1) peroxynitrite anion, formed as the product of •NO metabolism and superoxide radicals; (2) (myelo)peroxidase-catalyzed nitrogen dioxide radical (•NO2), a product of hydrogen peroxide and nitrite; and (3) nitrogen dioxide radical derived from nitric oxide in oxygenated buffers used in in vitro experimentation.
Although protein nitration has been recognized for a long time, its functional role in vivo is poorly understood. A wide variety of proteins involved in cardiovascular physiology are targets of tyrosine nitration, and the functional outcome for the targeted protein once modified is diverse, ranging from inactivation, which is most common, to gain of function. Proteins in the plasma, arterial wall, mitochondria, and sarcomere, many of which are involved in atherogenesis and vascular function, can be targeted. Some evidence suggests that protein nitration at tyrosine residues may serve as a marker of atherosclerotic heart disease.3 Nitration of tyrosine 294/295 in sarcoendoplasmic reticulum calcium ATPase has been linked with …