Biosynthesis of proresolving lipid mediators by vascular cells and tissues

Chatterjee, Anushree; Komshian, Sevan; Sansbury, Brian E.; Wu, Bian; Mottola, Giorgio; Chen, Mian; Spite, Matthew; Conte, Michael S.

doi:10.1096/fj.201700082r

Cited by 44 publications

(36 citation statements)

References 61 publications

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“…SPMs have been identified in atherosclerotic lesions of mice (20,94). In recent work, we demonstrated that isolated, ex vivo human artery segments and primary cultured human vascular cells generated D-series resolvins and maresins when the relevant fatty acid precursors (e.g., DHA, 17-hydroxydocosahexaenoic acid ) were made available, and in the absence of leukocytes (95). Furthermore, conditioned media from DHA-supplemented vascular cells blunted leukocyte adhesion to cytokine-activated ECs, in a receptor-dependent fashion (i.e., ALX/FPR2 and GPR32).…”

Section: Clinical Studies Of Pufa Supplementation In Vascular Diseasementioning

confidence: 95%

Pro-resolving lipid mediators in vascular disease

Conte¹,

Desai²,

Wu³

et al. 2018

Journal of Clinical Investigation

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Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis - conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for "resolution therapeutics" in vascular patients.

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Section: Clinical Studies Of Pufa Supplementation In Vascular Diseasementioning

confidence: 95%

Pro-resolving lipid mediators in vascular disease

Conte¹,

Desai²,

Wu³

et al. 2018

Journal of Clinical Investigation

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“…SPM have been identified in mouse atherosclerotic lesions (Fredman, Hellmann et al 2016, Viola, Lemnitzer et al 2016) where they correlate with histologic signs of plaque stability. More recently it was demonstrated that isolated human artery segments and primary cultured human vascular cells generate D-series resolvins in the presence of precursors (DHA,17-HDHA) (Chatterjee, Komshian et al 2017). Conditioned media from these DHA-supplemented vascular cells blunted leukocyte adhesion to activated EC, in a reaction that was attenuated by blocking the RvD1 receptors ALX and GPR32.…”

Section: Biosynthesis Of Spm In the Vasculature And Evidence For Recementioning

confidence: 99%

“…Third, biosynthesis pathways for both omega-3 and omega-6 fatty acids are complex and involve competition for enzymes to production various bioactive mediators (Levy, Clish et al 2001, Serhan 2007, Spite and Serhan 2010, Merched, Serhan et al 2011, Colas, Shinohara et al 2014, Serhan 2014, Poorani, Bhatt et al 2015) and this competition can produce isomers without proresolving actions (Dona, Fredman et al 2008, Spite, Norling et al 2009). Furthermore, similar pathways might play antagonistic roles in different cell types and/or different species (Wittwer and Hersberger 2007, Chatterjee, Komshian et al 2017) and additional factors such as aging (common in the atherosclerosis population) may alter the biosynthetic pathways (Halade, Kain et al 2016). An additional consideration is that oral administration of precursors might not produce adequate systemic or local amounts of specific bioactive mediators (Endo, Sano et al 2014), especially in the setting of a high cholesterol diet (Faggin, Puato et al 2000).…”

Section: Translation: Resolution Pharmacology In Vascular Injurymentioning

confidence: 99%

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

Mottola

Schaller

et al. 2017

Molecular Aspects of Medicine

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Acute vascular injury occurs in a number of important clinical contexts, including spontaneous disease-related events (e.g. plaque rupture, thrombosis) and therapeutic interventions such as angioplasty, stenting, or bypass surgery. Endothelial cell (EC) disruption exposes the underlying matrix, leading to a rapid deposition of platelets, coagulation proteins, and leukocytes. A thrombo-inflammatory response ensues characterized by leukocyte recruitment, vascular smooth muscle cell (VSMC) activation, and the elaboration of cytokines, reactive oxygen species and growth factors within the vessel wall. A resolution phase of vascular injury may be described in which leukocyte efflux, clearance of debris, and re-endothelialization occurs. VSMC migration and proliferation leads to the development of a thickened neointima that may lead to lumen compromise. Subsequent remodeling involves matrix protein deposition, and return of EC and VSMC to quiescence. Recent studies suggest that specialized proresolving lipid mediators (SPM) modulate key aspects of this response, and may constitute an endogenous homeostatic pathway in the vasculature. SPM exert direct effects on vascular cells that counteract inflammatory signals, reduce leukocyte adhesion, and inhibit VSMC migration and proliferation. These effects appear to be largely G-protein coupled receptor-dependent. Across a range of animal models of vascular injury, including balloon angioplasty, bypass grafting, and experimental aneurysm formation, SPM accelerate repair and reduce lesion formation. With bioactivity in the pM-nM range, a lack of discernible cytotoxicity, and a spectrum of vasculo-protective properties, SPM represent a novel class of vascular therapeutics. This review summarizes current research in this field, including a consideration of critical next steps and challenges in translation.

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“…Indeed, at the preclinical level, therapeutic administration of SPMs has shown to promote resolution of inflamed adipose tissue and to protect mice against obesity-associated complications such as insulin resistance and NAFLD (8)(9)(10)(11)(12). Moreover, recent findings have demonstrated that SPMs play a homeostatic role in the human vasculature (13). However, at present, clear proof that the production of SPMs is impaired in the systemic circulation of obese subjects is still lacking.…”

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confidence: 99%

Leukocytes from obese individuals exhibit an impaired SPM signature

et al. 2019

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Specialized proresolving mediators (SPMs) biosynthesized from docosahexaenoic acids (DHAs) including resolvins (Rvs), protectins, and maresins are potent endogenous autacoids that actively resolve inflammation, protect organs, and stimulate tissue regeneration. Our hypothesis was that failure of resolution programs may lead to unremitting inflammation in obesity, contributing to the development of metabolic comorbidities in this condition. Obese individuals with persistent low‐grade systemic inflammation showed reduced leukocyte production of the DHA‐derived monohydroxy fatty acid 17—hydroxy‐DHA (HDHA) and unbalanced formation of SPMs (in particular d‐series Rvs) accompanied by enhanced production of proinflammatory lipid mediators such as leukotriene B4. Mechanistic studies attributed this impairment to reduced 15‐lipoxygenase (LOX) activity rather than altered DHA cellular uptake. Moreover, leukocytes from obese individuals exhibited decreased 5‐LOX levels and reduced 5‐LOX Ser271 phosphorylation and distinct intracellular 5‐LOX redistribution. However, 15‐LOX appears to be the most critical factor for the deficient production of SPMs by obese leukocytes because the formation of d‐series Rvs was completely rescued by incubation with the intermediate precursor 17‐HDHA. These data provide proof of concept that administration of intermediate precursors of SPM biosynthesis (e.g., 17‐HDHA) could be more efficient in overriding impaired formation of these proresolving lipid mediators in conditions characterized by dysfunctional LOX activity, such as obesity.—López‐Vicario, C, Titos, E., Walker, M. E., Alcaraz‐Quiles, J., Casulleras, M., Durán‐Güell, M., Flores‐Costa, R., Pérez‐Romero, N., Forné, M., Dalli, J., Clària, J. Leukocytes from obese individuals exhibit an impaired SPM signature. FASEB J. 33, 7072–7083 (2019). http://www.fasebj.org

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Biosynthesis of proresolving lipid mediators by vascular cells and tissues

Cited by 44 publications

References 61 publications

Pro-resolving lipid mediators in vascular disease

Pro-resolving lipid mediators in vascular disease

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

Leukocytes from obese individuals exhibit an impaired SPM signature

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