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      Peroxynitrite-Mediated SIRT (Sirtuin)-1 Inactivation Contributes to Nicotine-Induced Arterial Stiffness in Mice

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          Abstract

          Inhibition of Sirtuin-1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, is linked to cigarette smoking-induced arterial stiffness, but the underlying mechanisms remain largely unknown. The aim of the present study was to determine the effects and mechanisms of nicotine, a major component of cigarette smoke, on SIRT1 activity and arterial stiffness. Arterial stiffness, peroxynitrite (ONOO − ) formation, SIRT1 expression and activity were monitored in mouse aortas of eight-week-old C57BL/6 mice (wild-type) or Sirt1- overexpressing ( Sirt1 Super ) mice with or without nicotine for 4 weeks. In aortas of wild-type mice, nicotine reduced SIRT1 protein and activity by ≈ 50% without affecting its mRNA levels. In those from Sirt1 Super mice, nicotine also markedly reduced SIRT1 protein and activity to the levels that were comparable to those in wild-type mice. Nicotine infusion significantly induced collagen I, fibronectin, and arterial stiffness in wild-type but not Sirt1 Super mice. Nicotine increased the levels of inducible nitric oxide synthase and the co-staining of SIRT1 and 3-nitrotyrosine, a footprint of ONOO − in aortas. Tempol, which ablated ONOO − by scavenging superoxide anion, reduced the effects of nicotine on SIRT1 and collagen. Mutation of zinc-binding cysteine 395 or 398 in SIRT1 into serine (C395S) or (C398S) abolished SIRT1 activity. Furthermore, ONOO − dose-dependently inhibited the enzyme and increased zinc release in recombinant SIRT1. Finally, we found SIRT1 inactivation by ONOO − activated the Yes-associated protein (YAP) resulting in abnormal extracellular matrix remodeling. Nicotine induces ONOO − , which selectively inhibits SIRT1 resulting in a YAP-mediated extracellular matrix remodeling.

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          Sirt1 protects against high-fat diet-induced metabolic damage.

          The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat diet-induced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipid-induced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1alpha, and lower activation of proinflammatory cytokines, such as TNFalpha and IL-6, via down-modulation of NFkappaB activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.
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            Physiology and pathophysiology of matrix metalloproteases

            Matrix metalloproteases (MMPs) comprise a family of enzymes that cleave protein substrates based on a conserved mechanism involving activation of an active site-bound water molecule by a Zn2+ ion. Although the catalytic domain of MMPs is structurally highly similar, there are many differences with respect to substrate specificity, cellular and tissue localization, membrane binding and regulation that make this a very versatile family of enzymes with a multitude of physiological functions, many of which are still not fully understood. Essentially, all members of the MMP family have been linked to disease development, notably to cancer metastasis, chronic inflammation and the ensuing tissue damage as well as to neurological disorders. This has stimulated a flurry of studies into MMP inhibitors as therapeutic agents, as well as into measuring MMP levels as diagnostic or prognostic markers. As with most protein families, deciphering the function(s) of MMPs is difficult, as they can modify many proteins. Which of these reactions are physiologically or pathophysiologically relevant is often not clear, although studies on knockout animals, human genetic and epigenetic, as well as biochemical studies using natural or synthetic inhibitors have provided insight to a great extent. In this review, we will give an overview of 23 members of the human MMP family and describe functions, linkages to disease and structural and mechanistic features. MMPs can be grouped into soluble (including matrilysins) and membrane-anchored species. We adhere to the ‘MMP nomenclature’ and provide the reader with reference to the many, often diverse, names for this enzyme family in the introduction.
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              Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects.

              In proteins, the nitration of tyrosine residues to 3-nitro-tyrosine represents an oxidative post-translational modification that disrupts nitric oxide ((•)NO) signaling and skews metabolism towards pro-oxidant processes. Indeed, excess levels of reactive oxygen species in the presence of (•)NO or (•)NO-derived metabolites lead to the formation of nitrating species such as peroxynitrite. Thus, protein 3-nitrotyrosine has been established as a biomarker of cell, tissue, and systemic "nitroxidative stress". Moreover, tyrosine nitration modifies key properties of the amino acid: phenol group pK(a), redox potential, hydrophobicity, and volume. Thus, the incorporation of a nitro group (-NO(2)) into protein tyrosines can lead to profound structural and functional changes, some of which contribute to altered cell and tissue homeostasis. In this Account, I describe our current efforts to define (1) biologically-relevant mechanisms of protein tyrosine nitration and (2) how this modification can cause changes in protein structure and function at the molecular level. First, I underscore the relevance of protein tyrosine nitration via free-radical-mediated reactions (in both peroxynitrite-dependent and -independent pathways) involving a tyrosyl radical intermediate (Tyr(•)). This feature of the nitration process is critical because Tyr(•) can follow various fates, including the formation of 3-nitrotyrosine. Fast kinetic techniques, electron paramagnetic resonance (EPR) studies, bioanalytical methods, and kinetic simulations have all assisted in characterizing and fingerprinting the reactions of tyrosine with peroxynitrite and one-electron oxidants and its further evolution to 3-nitrotyrosine. Recent findings show that nitration of tyrosines in proteins associated with biomembranes is linked to the lipid peroxidation process via a connecting reaction that involves the one-electron oxidation of tyrosine by lipid peroxyl radicals (LOO(•)). Second, immunochemical and proteomic-based studies indicate that protein tyrosine nitration is a selective process in vitro and in vivo, preferentially directed to a subset of proteins, and within those proteins, typically one or two tyrosine residues are site-specifically modified. The nature and site(s) of formation of the proximal oxidizing or nitrating species, the physicochemical characteristics of the local microenvironment, and the structural features of the protein account for part of this selectivity. How this relatively subtle chemical modification in one tyrosine residue can sometimes cause dramatic changes in protein activity has remained elusive. Herein, I analyze recent structural biology data of two pure and homogenously nitrated mitochondrial proteins (i.e., cytochrome c and manganese superoxide dismutase, MnSOD) to illustrate regioselectivity and structural effects of tyrosine nitration and subsequent impact in protein loss- or even gain-of-function.
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                Author and article information

                Journal
                Arteriosclerosis, Thrombosis, and Vascular Biology
                ATVB
                Ovid Technologies (Wolters Kluwer Health)
                1079-5642
                1524-4636
                July 2019
                July 2019
                : 39
                : 7
                : 1419-1431
                Affiliations
                [1 ]From the Center for Molecular and Translational Medicine, Georgia State University, Atlanta.
                Article
                10.1161/ATVBAHA.118.312346
                6613385
                31092012
                90197d12-6564-4108-a116-63342c65fe45
                © 2019
                History

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