Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed.

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Heterotropic association of tissue transglutaminase (TG2) with extracellular matrix-associated fibronectin (FN) can restore the adhesion of fibroblasts when the integrin-mediated direct binding to FN is impaired using RGD-containing peptide. We demonstrate that the compensatory effect of the TG-FN complex in the presence of RGD-containing peptides is mediated by TG2 binding to the heparan sulfate chains of the syndecan-4 cell surface receptor. This binding mediates activation of protein kinase C␣ (PKC␣) and its subsequent interaction with ␤ 1 integrin since disruption of PKC␣ binding to ␤ 1 integrins with a cell-permeant competitive peptide inhibits cell adhesion and the associated actin stress fiber formation. Cell signaling by this process leads to the activation of focal adhesion kinase and ERK1/2 mitogen-activated protein kinases. Fibroblasts deficient in Raf-1 do not respond fully to the TG-FN complex unless either the full-length kinase competent Raf-1 or the kinase-inactive domain of Raf-1 is reintroduced, indicating the involvement of the Raf-1 protein in the signaling mechanism. We propose a model for a novel RGD-independent cell adhesion process that could be important during tissue injury and/or remodeling whereby TG-FN binding to syndecan-4 activates PKC␣ leading to its association with ␤ 1 integrin, reinforcement of actin-stress fiber organization, and MAPK pathway activation. Tissue transglutaminase (TG2)2 belongs to a family of enzymes that in the presence of Ca 2ϩ catalyze the post-translational modification of proteins either by covalent cross-linking or through the incorporation of primary amines. TG2 has a GTP binding/hydrolysis site that negatively modulates the Ca 2ϩ -dependent transamidating activity of the enzyme by obstructing access to the active site (1). As a consequence, the enzyme is likely to be inactive under normal Ca 2ϩ homeostasis. TG2 localizes mainly in the cytoplasm, yet recent reports also suggest its presence in the nucleus, mitochondria, at the cell surface, and in the extracellular matrix (ECM) (1-3). TG2 is translocated to the plasma membrane and was subsequently deposited into the ECM via a non-classical secretory mechanism reportedly dependent on active site conformation and on an intact N-terminal ␤-sandwich domain (4, 5) as well as on its possible association with integrins (6). Deposition of the enzyme into the ECM after cell damage and stress is important in the remodeling and/or stabilization of the several ECM proteins, such as FN (7,8). FN is particularly interesting since TG2 binds to this ECM protein with high affinity promoting wideranging effects on cell-matrix interactions, including the regulation of cell adhesion and migration, matrix assembly, and adhesion-dependent signaling (6,7,9).Cell adhesion to FN involves a series of coordinated signaling events orchestrated by numerous transmembrane receptors including the integrins and the superfamily of cell-surface proteoglycans (10, 11). The identity of the receptor-ligand pairing defines the composition of f...

Intracellular proteolysis is critical to maintain timely degradation of altered proteins including oxidized proteins. This review attempts to summarize the most relevant findings about oxidant protein modification, as well as the impact of reactive oxygen species on the proteolytic systems that regulate cell response to an oxidant environment: the ubiquitin-proteasome system (UPS), autophagy and the unfolded protein response (UPR). In the presence of an oxidant environment, these systems are critical to ensure proteostasis and cell survival. An example of altered degradation of oxidized proteins in pathology is provided for neurodegenerative diseases. Future work will determine if protein oxidation is a valid target to combat proteinopathies.

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In fibrotic conditions increases in TG2 activity has been linked to an increase in the deposition of extracellular matrix proteins. Using TG2 transfected Swiss 3T3 fibroblasts expressing TG2 under the control of the tetracycline-regulated inducible promoter, we demonstrate that induction of TG2 not only stimulates an increase in collagen and fibronectin deposition but also an increase in the expression of these proteins. Increased TG2 expression in these fibroblasts led to NF-B activation, resulting in the increased expression of transforming growth factor (TGF) ␤ 1 . In addition, cells overexpressing TG2 demonstrated an increase in biologically active TGF␤ 1 in the extracellular environment. A specific site-directed inhibitor of TG abolished the NF-B and TGF␤1 activation and the subsequent elevation in the synthesis and deposition of extracellular matrix proteins, confirming that this process depends on the induction of transglutaminase activity. Treatment of TG2-induced fibroblasts with nontoxic doses of nitric oxide donor S-nitroso-N-acetylpenicillamine resulted in decreased TG2 activity and apprehension of the inactive enzyme on the cell surface. This was paralleled by a reduction in activation of NF-B and TGF␤ 1 production with a subsequent decrease in collagen expression and deposition. These findings support a role for NO in the regulation of TG2 function in the extracellular environment.

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