Abstract:The production of various reactive oxidant species in excess of endogenous antioxidant defense mechanisms promotes the development of a state of oxidative stress, with significant biological consequences. In recent years, evidence has emerged that oxidative stress plays a crucial role in the development and perpetuation of inflammation, and thus contributes to the pathophysiology of a number of debilitating illnesses, such as cardiovascular diseases, diabetes, cancer, or neurodegenerative processes. Oxidants affect all stages of the inflammatory response, including the release by damaged tissues of molecules acting as endogenous danger signals, their sensing by innate immune receptors from the Toll-like (TLRs) and the NOD-like (NLRs) families, and the activation of signaling pathways initiating the adaptive cellular response to such signals. In this article, after summarizing the basic aspects of redox biology and inflammation, we review in detail the current knowledge on the fundamental connections between oxidative stress and inflammatory processes, with a special emphasis on the danger molecule highmobility group box-1, the TLRs, the NLRP-3 receptor, and the inflammasome, as well as the transcription factor nuclear factor-κB.

Recent evidence suggests that the heart possesses a greater regeneration capacity than previously thought. In the present study, we isolated undifferentiated precursors from the cardiac nonmyocyte cell population of neonatal hearts, expanded them in culture, and induced them to differentiate into functional cardiomyocytes. These cardiac precursors appear to express stem cell antigen-1 and demonstrate characteristics of multipotent precursors of mesodermal origin. Following infusion into normal recipients, these cells home to the heart and participate in physiological and pathophysiological cardiac remodeling. Cardiogenic differentiation in vitro and in vivo depends on FGF-2. Interestingly, this factor does not control the number of precursors but regulates the differentiation process. These findings suggest that, besides its angiogenic actions, FGF-2 could be used in vivo to facilitate the mobilization and differentiation of resident cardiac precursors in the treatment of cardiac diseases.

Abbreviations used: BNP, brain natriuretic peptide; CPC, cardiac precursor cell; Hes, Hairy/ enhancer of split; MZB, marginal zone B; Sca, stem cell antigen.A. Croquelois, A.A. Domenighetti, and M. Nemir contributed equally to this paper.

Myocardial infarction (MI) induces a sterile inflammatory response which contributes to adverse cardiac remodeling. The initiating mechanisms of this response remain incompletely defined. We found that necrotic cardiomyocytes released a heat-labile pro-inflammatory signal activating MAP kinases and NF-κB in cardiac fibroblasts, with secondary production of cytokines. This response was abolished in Myd88−/− fibroblasts, but was unaffected in nlrp3-deficient fibroblasts. Despite MyD88-dependency, the response was TLR-independent, as explored in TLR reporter cells, pointing to the implication of the IL-1 pathway. Indeed, necrotic cardiomyocytes released IL-1α, but not IL-1β, and the immune activation of cardiac fibroblasts was abrogated by an IL-1 receptor antagonist and an IL-1α blocking antibody. Moreover, immune responses triggered by necrotic Il1a−/− cardiomyocytes were markedly reduced. In vivo, mice exposed to MI released IL-1α in the plasma, and post-ischemic inflammation was attenuated in Il1a−/− mice. Thus, our findings identify IL-1α as a crucial early danger signal triggering post-MI inflammation.

In rats with large myocardial infarction, progression from compensated remodeling to overt heart failure is associated with upregulation of GLUT-1 and downregulation of MCAD in both the peri-infarction region and the septum.

Redox-based mechanisms play critical roles in the regulation of multiple cellular functions. NF-B, a master regulator of inflammation, is an inducible transcription factor generally considered to be redox-sensitive, but the modes of interactions between oxidant stress and NF-B are incompletely defined. Here, we show that oxidants can either amplify or suppress NF-B activation in vitro by interfering both with positive and negative signals in the NF-B pathway. NF-B activation was evaluated in lung A549 epithelial cells stimulated with tumor necrosis factor ␣ (TNF␣), either alone or in combination with various oxidant species, including hydrogen peroxide or peroxynitrite. Exposure to oxidants after TNF␣ stimulation produced a robust and long lasting hyperactivation of NF-B by preventing resynthesis of the NF-B inhibitor IB, thereby abrogating the major negative feedback loop of NF-B. This effect was related to continuous activation of inhibitor of B kinase (IKK), due to persistent IKK phosphorylation consecutive to oxidant-mediated inactivation of protein phosphatase 2A. In contrast, exposure to oxidants before TNF␣ stimulation impaired IKK phosphorylation and activation, leading to complete prevention of NF-B activation. Comparable effects were obtained when interleukin-1␤ was used instead of TNF␣ as the NF-B activator. This study demonstrates that the influence of oxidants on NF-B is entirely context-dependent, and that the final outcome (activation versus inhibition) depends on a balanced inhibition of protein phosphatase 2A and IKK by oxidant species. Our findings provide a new conceptual framework to understand the role of oxidant stress during inflammatory processes.Oxidant stress is a critical pathophysiological mechanism that stands at the foreground of a number of inflammatory diseases. In such conditions, highly reactive oxygen and nitrogen species exert their biological activity by inflicting various oxidative damages to biomolecules and by modulating the activity of redox-sensitive signal transduction pathways (1). The transcription factor nuclear factor B (NF-B)2 is a master regulator of inflammation and apoptosis, which is considered a prototypical example of such sensitivity to oxidant stress (2). NF-B is a family of dimeric proteins normally retained in the cytoplasm of nonstimulated cells, bound to inhibitory proteins, the IBs (3). The critical step in NF-B activation relies on its dissociation from the IB protein, resulting from stimulus-induced phosphorylation of IB, followed by its polyubiquitination and proteasomal degradation. IB itself is phosphorylated by IB kinase (IKK), composed of a heterodimer of two catalytic subunits, IKK␣/␤, and a regulatory subunit, IKK␥ (4). A considerable variety of stimuli lead to IKK activation and downstream NF-B signaling, comprising inflammatory cytokines, various microbial components, as well as genotoxic, physical, or chemical stress factors (5).Since the first report by Schreck et al. (6) that NF-B could be activated directly by H 2 O 2 in a subclone of Ju...

Brain natriuretic peptide (BNP) contributes to heart formation during embryogenesis. After birth, despite a high number of studies aimed at understanding by which mechanism(s) BNP reduces myocardial ischemic injury in animal models, the actual role of this peptide in the heart remains elusive. In this study, we asked whether BNP treatment could modulate the proliferation of endogenous cardiac progenitor cells (CPCs) and/or their differentiation into cardiomyocytes. CPCs expressed the NPR-A and NPR-B receptors in neonatal and adult hearts, suggesting their ability to respond to BNP stimulation. BNP injection into neonatal and adult unmanipulated mice increased the number of newly formed cardiomyocytes (neonatal: +23 %, p = 0.009 and adult: +68 %, p = 0.0005) and the number of proliferating CPCs (neonatal: +142 %, p = 0.002 and adult: +134 %, p = 0.04). In vitro, BNP stimulated CPC proliferation via NPR-A and CPC differentiation into cardiomyocytes via NPR-B. Finally, as BNP might be used as a therapeutic agent, we injected BNP into mice undergoing myocardial infarction. In pathological conditions, BNP treatment was cardioprotective by increasing heart contractility and reducing cardiac remodelling. At the cellular level, BNP stimulates CPC proliferation in the non-infarcted area of the infarcted hearts. In the infarcted area, BNP modulates the fate of the endogenous CPCs but also of the infiltrating CD45(+) cells. These results support for the first time a key role for BNP in controlling the progenitor cell proliferation and differentiation after birth. The administration of BNP might, therefore, be a useful component of therapeutic approaches aimed at inducing heart regeneration.

These findings indicate that peroxynitrite represents a key mediator of HMGB1 overexpression and release by cardiac cells and provide a novel mechanism linking myocardial oxidative/nitrosative stress with post-infarction myocardial inflammation.