Dietary ω-3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease.
The anemia of sickle cell disease is associated with a severe inflammatory vasculopathy and endothelial dysfunction, which leads to painful and life-threatening clinical complications. Growing evidence supports the anti-inflammatory properties of ω-3 fatty acids in clinical models of endothelial dysfunction. Promising but limited studies show potential therapeutic effects of ω-3 fatty acid supplementation in sickle cell disease. Here, we treated humanized healthy and sickle cell mice for 6 weeks with ω-3 fatty acid diet (fish-oil diet). We found that a ω-3 fatty acid diet: (i) normalizes red cell membrane ω-6/ω-3 ratio; (ii) reduces neutrophil count; (iii) decreases endothelial activation by targeting endothelin-1 and (iv) improves left ventricular outflow tract dimensions. In a hypoxia-reoxygenation model of acute vaso-occlusive crisis, a ω-3 fatty acid diet reduced systemic and local inflammation and protected against sickle cell-related end-organ injury. Using isolated aortas from sickle cell mice exposed to hypoxia-reoxygenation, we demonstrated a direct impact of a ω-3 fatty acid diet on vascular activation, inflammation, and anti-oxidant systems. Our data provide the rationale for ω-3 dietary supplementation as a therapeutic intervention to reduce vascular dysfunction in sickle cell disease.
Department of Surgery and The Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Brian T
BT
Kalish
Department of Medicine, University of Verona-AOUI Verona, Policlinico GB Rossi, Verona, Italy.
Alessandro
A
Matte
Department of Biochemistry, University Federico II, Naples, Italy.
Immacolata
I
Andolfo
Department of Biochemistry, University Federico II, Naples, Italy.
Achille
A
Iolascon
Departments of Pathology and Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Olga
O
Weinberg
Molecular Biotechnology Center and Department of Molecular Biotechology and Health Science, University of Turin, Italy.
Alessandra
A
Ghigo
Molecular Biotechnology Center and Department of Molecular Biotechology and Health Science, University of Turin, Italy.
James
J
Cimino
Department of Medicine, University of Verona-AOUI Verona, Policlinico GB Rossi, Verona, Italy.
Angela
A
Siciliano
Molecular Biotechnology Center and Department of Molecular Biotechology and Health Science, University of Turin, Italy.
Emilio
E
Hirsch
Department of Medicine, University of Verona-AOUI Verona, Policlinico GB Rossi, Verona, Italy.
Enrica
E
Federti
Department of Surgery and The Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Mark
M
Puder
Departments of Pathology and Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA carlo.brugnara@childrens.harvard.edu.
Carlo
C
Brugnara
Department of Medicine, University of Verona-AOUI Verona, Policlinico GB Rossi, Verona, Italy.
Lucia
L
De Franceschi
D000755:Anemia, Sickle Cell / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000473:pathology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000009:adverse effects
D000893:Anti-Inflammatory Agents; D019332:Endothelin-1; D015525:Fatty Acids, Omega-3; D010100:Oxygen