Effects of endothelin-1 on fibroblasts from type 2 diabetic patients: Possible role in wound healing and tissue repair.
Endothelin-1 (ET-1) promotes the contractile ability of fibroblasts, essential for wound closure and reconstitution of the dermis. Wound healing is impaired in type 2 diabetic patients (D). We compared the effect of ET-1 on proliferative transforming growth factor (TGFbeta(1)) expression, fibronectin and laminin release), differentiative [alpha-smooth muscle actin (alpha-SMA) expression] and inflammatory [monocyte chemo-attractant protein (MCP-1) and interleukin-6 (IL-6) expression] responses in skin fibroblasts of healthy subjects (C) and D, testing the relative role of ET(A) and ET(B) receptors in mediating these responses. ET-1 did not influence TGFbeta(1), fibronectin or laminin production. alpha-SMA was more abundant and more stimulated in D, as well as MCP-1 and IL-6 expression and release. These effects were prevented by BMS-182874, selective antagonist of ET(A), more abundant than ET(B) in both cell strains and whose expression rose more in D than C upon stimulation with ET-1. This peculiar pattern of responses to ET-1, presumably acquired during the chronic in vivo exposure to hyperglycemia along the natural history of the disease, may partially explain the increased susceptibility of D to chronic ulcerations.
Solini
Anna
A
Department of Internal Medicine, University of Pisa, Pisa, Italy. a.solini@med.unipi.it
Santini
Eleonora
E
Madec
Stephanie
S
Cuccato
Sabina
S
Ferrannini
Ele
E
D000199:Actins / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003619:Dansyl Compounds / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007797:Laminin / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology*
D000199:Actins; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003619:Dansyl Compounds; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005353:Fibronectins; C508600:IL6 protein, human; D015850:Interleukin-6; D007797:Laminin; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D053773:Transforming Growth Factor beta1; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide