Protein nitration in placenta - functional significance

Abstract

Crucial roles of the placenta are disrupted in early and mid-trimester pregnancy loss, preeclampsia, eclampsia and intrauterine growth restriction. The pathophysiology of these disorders includes a relative hypoxia of the placenta, ischemia/reperfusion injury, an inflammatory response and oxidative stress. Reactive oxygen species including nitric oxide (NO), carbon monoxide and superoxide have been shown to participate in trophoblast invasion, regulation of placental vascular reactivity and other events. Superoxide, which regulates expression of redox sensitive genes, has been implicated in up-regulation of transcription factors, antioxidant production, angiogenesis, proliferation and matrix remodeling. When superoxide and nitric oxide are present in abundance, their interaction yields peroxynitrite a potent pro-oxidant, but also alters levels of nitric oxide, which in turn affect physiological functions. The peroxynitrite anion is extremely unstable thus evidence of its formation in vivo has been indirect via the occurrence of nitrated moieties including nitrated lipids and nitrotyrosine residues in proteins. Formation of 3-nitrotyrosine (protein nitration) is a "molecular fingerprint" of peroxynitrite formation. Protein nitration has been widely reported in a number of pathological states associated with inflammation but is reported to occur in normal physiology and is thought of as a prevalent, functionally relevant post-translational modification of proteins. Nitration of proteins can give either no effect, a gain or a loss of function. Nitration of a range of placental proteins is found in normal pregnancy but increased in pathologic pregnancies. Evidence is presented for nitration of placental signal transduction enzymes and transporters. The targets and extent of nitration of enzymes, receptors, transporters and structural proteins may markedly influence placental cellular function in both physiologic and pathologic settings.

Figure 1. Rate Constants for the Interaction of Nitric Oxide and Superoxide and Breakdown of Superoxide by SOD

The rate constant for peroxynitrite formation is greater than that of dismutation of superoxide thus NO outcompetes SOD for superoxide to favor peroxynitrite formation.

Figure 2. Inhibitory Effects of Peroxynitrite on iNOS, Xanthine Oxidase and MnSOD

By feedback inhibtion of the activity of iNOS, XO and MnSOD, peroxynitrite can either inhibit (iNOS or XO) or promote (MnSOD) its own formation

Figure 3. Targets for Protein Nitration in the Placenta

Tyrosine nitration of key regulatory molecules in the placenta may potentially alter placental function