Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Kelley, Eric E.; Baust, Jeff; Bonacci, Gustavo; Golin-Bisello, Franca; Devlin, Jason; Croix, Claudette M. St.; Watkins, Simon C.; Gor, Sonia; Cantú‐Medellín, Nadiezhda; Weidert, Eric R.; Frisbee, Jefferson C.; Gladwin, Mark T.; Champion, Hunter C.; Freeman, Bruce Α.; Khoo, Nicholas K.H.

doi:10.1093/cvr/cvt341

Cited by 82 publications

(87 citation statements)

References 41 publications

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“…gated nitroalkene moiety (Scheme 1) modulate its intrinsic reactivity toward thiolate attack (23,26). In particular, for nitroalkene fatty acids the alkyl/carboxyl(ate) chains are expected to increase the reactivity toward thio-Michael addition with respect to the model system studied here, without altering the mechanism 7 leading to a more pronounced charge reorganization between partners at the C ␤ /C ␦ adduction TSs, closer to the expectations from the ␤ nuc values derived from experimental data. A similar rationale applies to bond forming/ breaking at each TS, for which Wiberg bond indices (WBIs) of 0.27/0.15 for the nascent S⅐⅐⅐C ␤ /S⅐⅐⅐C ␦ bonds imply advances of 28 or 16% at each reaction involving the model compounds.…”

Section: Correlations With Thiol Pk a Suggest That The Thiolate Partisupporting

confidence: 75%

The Chemical Basis of Thiol Addition to Nitro-conjugated Linoleic Acid, a Protective Cell-signaling Lipid

Turell

Vitturi

Coitiño

et al. 2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichNitroalkene fatty acids are formed in vivo and exert protective and anti-inflammatory effects via reversible Michael addition to thiol-containing proteins in key signaling pathways. Nitro-conjugated linoleic acid (NO 2 -CLA) is preferentially formed, constitutes the most abundant nitrated fatty acid in humans, and contains two carbons that could potentially react with thiols, modulating signaling actions and levels. In this work, we examined the reactions of NO 2 -CLA with low molecular weight thiols (glutathione, cysteine, homocysteine, cysteinylglycine, and ␤-mercaptoethanol) and human serum albumin. Reactions followed reversible biphasic kinetics, consistent with the presence of two electrophilic centers in NO 2 -CLA located on the ␤-and ␦-carbons with respect to the nitro group. The differential reactivity was confirmed by computational modeling of the electronic structure. The rates (k on and k off ) and equilibrium constants for both reactions were determined for different thiols. LC-UV-Visible and LC-MS analyses showed that the fast reaction corresponds to ␤-adduct formation (the kinetic product), while the slow reaction corresponds to the formation of the ␦-adduct (the thermodynamic product). The pH dependence of the rate constants, the correlation between intrinsic reactivity and thiol pK a , and the absence of deuterium solvent kinetic isotope effects suggested stepwise mechanisms with thiolate attack on NO 2 -CLA as rate-controlling step. Computational modeling supported the mechanism and revealed additional features of the transition states, anionic intermediates, and final neutral products. Importantly, the detection of cysteine-␦-adducts in human urine provided evidence for the biological relevance of this reaction. Finally, human serum albumin was found to bind NO 2 -CLA both non-covalently and to form covalent adducts at Cys-34, suggesting potential modes for systemic distribution. These results provide new insights into the chemical basis of NO 2 -CLA signaling actions.

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Section: Correlations With Thiol Pk a Suggest That The Thiolate Partisupporting

confidence: 75%

The Chemical Basis of Thiol Addition to Nitro-conjugated Linoleic Acid, a Protective Cell-signaling Lipid

Turell

Vitturi

Coitiño

et al. 2017

Journal of Biological Chemistry

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“…Negative control subjects included normoxia-maintained male agematched animals (5,14). Hemodynamic and histochemical analyses were performed as described (5,19). Blinded analysis of small PAs (25-150 mm outer diameter) was performed as described (5,20).…”

Section: What This Study Adds To Thementioning

confidence: 99%

HIPPO–Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension

Kudryashova

Goncharov

Pena

et al. 2016

Am J Respir Crit Care Med

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105

183

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Rationale: Enhanced proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) are key pathophysiologic components of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH).Objectives: To determine the role and therapeutic relevance of HIPPO signaling in PAVSMC proliferation/apoptosis imbalance in PAH.Methods: Primary distal PAVSMCs, lung tissue sections from unused donor (control) and idiopathic PAH lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. Measurements and Main Results:Immunohistochemical and immunoblot analyses demonstrated that the HIPPO central component large tumor suppressor 1 (LATS1) is inactivated in small remodeled pulmonary arteries (PAs) and distal PAVSMCs in idiopathic PAH. Molecular-and pharmacology-based analyses revealed that LATS1 inactivation and consequent up-regulation of its reciprocal effector Yes-associated protein (Yap) were required for activation of mammalian target of rapamycin (mTOR)-Akt, accumulation of HIF1a, Notch3 intracellular domain and b-catenin, deficiency of proapoptotic Bim, increased proliferation, and survival of human PAH PAVSMCs. LATS1 inactivation and up-regulation of Yap increased production and secretion of fibronectin that upregulated integrin-linked kinase 1 (ILK1). ILK1 supported LATS1 inactivation, and its inhibition reactivated LATS1, down-regulated Yap, suppressed proliferation, and promoted apoptosis in PAH, but not control PAVSMCs. PAVSM in small remodeled PAs from rats and mice with SU5416/hypoxia-induced PH showed downregulation of LATS1 and overexpression of ILK1. Treatment of mice with selective ILK inhibitor Cpd22 at Days 22-35 of SU5416/hypoxia exposure restored LATS1 signaling and reduced established pulmonary vascular remodeling and PH.Conclusions: These data report inactivation of HIPPO/LATS1, self-supported via Yap-fibronectin-ILK1 signaling loop, as a novel mechanism of self-sustaining proliferation and apoptosis resistance of PAVSMCs in PAH and suggest a new potential target for therapeutic intervention.

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“…Importantly, NO 2 -FA appears to target specific proteins [48]. Although which RNS predominate the reaction is not known, NO 2 -FA production occurs in pathological conditions, such as cardiac ischemia [49], pulmonary hypertension [50], and diabetes [50, 51]. …”

Section: Mode Of Action Of Nitric Oxidementioning

confidence: 99%

Nitric oxide in liver diseases

Iwakiri

Kim

2015

Trends in Pharmacological Sciences

226

177

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Nitric oxide (NO) and its derivatives play important roles in the physiology and pathophysiology of the liver. Despite its diverse and complicated roles, certain patterns of the effect of NO on the pathogenesis and progression of liver diseases are observed. In general, NO derived from endothelial NO synthase (eNOS) in liver sinusoidal endothelial cells (LSECs) is protective against disease development, while inducible NOS (iNOS)-derived NO contributes to pathological processes. This review addresses the roles of NO in the development of various liver diseases with a focus on recently published articles. We present here two recent advances in understanding NO-mediated signaling, nitrated fatty acids and S-guanylation, and conclude with suggestions on future directions of NO-related studies on the liver.

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Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Abstract: These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.

Cited by 82 publications

References 41 publications

The Chemical Basis of Thiol Addition to Nitro-conjugated Linoleic Acid, a Protective Cell-signaling Lipid

The Chemical Basis of Thiol Addition to Nitro-conjugated Linoleic Acid, a Protective Cell-signaling Lipid

HIPPO–Integrin-linked Kinase Cross-Talk Controls Self-Sustaining Proliferation and Survival in Pulmonary Hypertension

Nitric oxide in liver diseases

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