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Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension

Di Pietro, Paola ; Carrizzo, Albino ; Sommella, Eduardo ; Oliveti, Marco ; Iacoviello, Licia ; Di Castelnuovo, Augusto ; Acernese, Fausto ; Damato, Antonio ; De Lucia, Massimiliano ; Merciai, Fabrizio ; Iesu, Paola ; Venturini, Eleonora ; Izzo, Raffaele ; Trimarco, Valentina ; Ciccarelli, Michele ; Giugliano, Giuseppe ; Carnevale, Roberto ; Cammisotto, Vittoria ; Migliarino, Serena ; Virtuoso, Nicola ; Strianese, Andrea ; Izzo, Viviana ; Campiglia, Pietro ; Ciaglia, Elena ; Levkau, Bodo ; Puca, Annibale A ; Vecchione, Carmine

The Journal of clinical investigation, 2022-02, Vol.132 (3), p.1-16 [Periódico revisado por pares]

United States: American Society for Clinical Investigation

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Título:
Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension
Autor: Di Pietro, Paola ; Carrizzo, Albino ; Sommella, Eduardo ; Oliveti, Marco ; Iacoviello, Licia ; Di Castelnuovo, Augusto ; Acernese, Fausto ; Damato, Antonio ; De Lucia, Massimiliano ; Merciai, Fabrizio ; Iesu, Paola ; Venturini, Eleonora ; Izzo, Raffaele ; Trimarco, Valentina ; Ciccarelli, Michele ; Giugliano, Giuseppe ; Carnevale, Roberto ; Cammisotto, Vittoria ; Migliarino, Serena ; Virtuoso, Nicola ; Strianese, Andrea ; Izzo, Viviana ; Campiglia, Pietro ; Ciaglia, Elena ; Levkau, Bodo ; Puca, Annibale A ; Vecchione, Carmine
Assuntos: Adaptor Proteins, Vesicular Transport - genetics ; Adaptor Proteins, Vesicular Transport - metabolism ; Animals ; Arteries ; Biological markers ; Blood pressure ; Cardiovascular disease ; CYBB protein ; Development and progression ; Endothelium ; Endothelium, Vascular - injuries ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - pathology ; Endothelium, Vascular - physiopathology ; Enzymes ; Health aspects ; Homeostasis ; Human Umbilical Vein Endothelial Cells - metabolism ; Humans ; Hydrolases ; Hypertension ; Hypertension - genetics ; Hypertension - metabolism ; Hypertension - physiopathology ; Kinases ; Lipids ; Lysophospholipids - genetics ; Lysophospholipids - metabolism ; Membrane proteins ; Metabolism ; Mice ; Mice, Knockout ; NAD(P)H oxidase ; Oxidative stress ; Pathogenesis ; Peptides ; Physiological aspects ; Plasma ; Plasma levels ; Proteins ; Signal Transduction ; Sphingolipids ; Sphingomyelin phosphodiesterase ; Sphingomyelin Phosphodiesterase - genetics ; Sphingomyelin Phosphodiesterase - metabolism ; Sphingosine - analogs & derivatives ; Sphingosine - genetics ; Sphingosine - metabolism ; Sphingosine 1-phosphate ; Sphingosine kinase ; Vascular biology ; Vascular system ; Vein & artery diseases
É parte de: The Journal of clinical investigation, 2022-02, Vol.132 (3), p.1-16
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.
Editor: United States: American Society for Clinical Investigation
Idioma: Inglês

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Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension

United States: American Society for Clinical Investigation

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