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

  • J Clin Invest. 2022 Feb 1;132(3):e146343. doi: 10.1172/JCI146343.
Paola Di Pietro  1 ,  Albino Carrizzo  1  2 ,  Eduardo Sommella  3 ,  Marco Oliveti  1 ,  Licia Iacoviello  4  5 ,  Augusto Di Castelnuovo  6 ,  Fausto Acernese  3 ,  Antonio Damato  2 ,  Massimiliano De Lucia  2 ,  Fabrizio Merciai  3  7 ,  Paola Iesu  1 ,  Eleonora Venturini  2 ,  Raffaele Izzo  8 ,  Valentina Trimarco  9 ,  Michele Ciccarelli  1 ,  Giuseppe Giugliano  8 ,  Roberto Carnevale  6  10 ,  Vittoria Cammisotto  11 ,  Serena Migliarino  12 ,  Nicola Virtuoso  1 ,  Andrea Strianese  1 ,  Viviana Izzo  1 ,  Pietro Campiglia  3  13 ,  Elena Ciaglia  1 ,  Bodo Levkau  14 ,  Annibale A Puca  1  15 ,  Carmine Vecchione  1  2
Affiliations
  • 1. Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana" University of Salerno, Baronissi, Italy.
  • 2. Department of Vascular Physiopathology, IRCCS Neuromed, Pozzilli, Italy.
  • 3. Department of Pharmacy, School of Pharmacy, University of Salerno, Fisciano, Italy.
  • 4. Department of Medicine and Surgery, Research Center in Epidemiology and Preventive Medicine (EPIMED), University of Insubria, Varese, Italy.
  • 5. Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy.
  • 6. Mediterranea Cardiocentro, Naples, Italy.
  • 7. PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, Italy.
  • 8. Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
  • 9. Department of Neuroscience, Reproductive Sciences and Dentistry, University of Naples Federico II, Naples, Italy.
  • 10. Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
  • 11. Department of General Surgery and Surgical Speciality Paride Stefanini, Sapienza University of Rome, Rome, Italy.
  • 12. Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
  • 13. European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy.
  • 14. Institute for Molecular Medicine III, Heinrich-Heine-University, Medical Faculty, Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany.
  • 15. Ageing Unit, IRCCS MultiMedica, Milan, Italy.
PMID: 35104805 DOI: 10.1172/JCI146343
Abstract

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.

Keywords
Cardiovascular disease; Hypertension; Vascular Biology.
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