Albino Carrizzo1, Paola Lenzi1, Claudio Procaccini1, Antonio Damato1, Francesca Biagioni1, Mariateresa Ambrosio1, Giuseppina Amodio1, Paolo Remondelli1, Carmine Del Giudice1, Raffaele Izzo1, Alberto Malovini1, Luigi Formisano1, Vincenzo Gigantino1, Michele Madonna1, Annibale A Puca1, Bruno Trimarco1, Giuseppe Matarese1, Francesco Fornai1, Carmine Vecchione2. 1. From IRCCS Neuromed, Pozzilli, Italy (A.C., A.D., F.B., M.A., M.M., F.F., C.V.); University of Pisa, Department of Human Morphology and Applied Biology, Italy (P.L., F.F.); Laboratory of Immunology, Institute of Experimental Endocrinology and Oncology, National Research Council of Italy (IEOS-CNR), c/o Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Napoli, Italy; (C.P., V.G.); University of Salerno, Department of Pharmaceutical Sciences, Fisciano (Salerno), Italy (G.A.); University of Salerno, Medicine and Surgery, Baronissi (Salerno), Italy (G.A., P.R., A.A.P., G.M., C.V.); Hypertension Research Center and Department of Advanced Biomedical Sciences (D.G.C., B.T.) and Department of Translational Medical Sciences (R.I.), University of Naples "Federico II", Napoli, Italy; University of Pavia, Department of Industrial and Information Engineering, Italy (A. Malovini); Department of Science and Technology, University of Sannio, Benevento, Italy (L.F.); Pathology Unit, "Istituto Nazionale Tumori, IRCCS, Fondazione Pascale," Naples, Italy (V.G.); and IRCCS Multimedica, Milan, Italy (A.A.P., G.M.). 2. From IRCCS Neuromed, Pozzilli, Italy (A.C., A.D., F.B., M.A., M.M., F.F., C.V.); University of Pisa, Department of Human Morphology and Applied Biology, Italy (P.L., F.F.); Laboratory of Immunology, Institute of Experimental Endocrinology and Oncology, National Research Council of Italy (IEOS-CNR), c/o Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Napoli, Italy; (C.P., V.G.); University of Salerno, Department of Pharmaceutical Sciences, Fisciano (Salerno), Italy (G.A.); University of Salerno, Medicine and Surgery, Baronissi (Salerno), Italy (G.A., P.R., A.A.P., G.M., C.V.); Hypertension Research Center and Department of Advanced Biomedical Sciences (D.G.C., B.T.) and Department of Translational Medical Sciences (R.I.), University of Naples "Federico II", Napoli, Italy; University of Pavia, Department of Industrial and Information Engineering, Italy (A. Malovini); Department of Science and Technology, University of Sannio, Benevento, Italy (L.F.); Pathology Unit, "Istituto Nazionale Tumori, IRCCS, Fondazione Pascale," Naples, Italy (V.G.); and IRCCS Multimedica, Milan, Italy (A.A.P., G.M.). cvecchione@unisa.it.
Abstract
BACKGROUND: Pentraxin 3 (PTX3), the prototype of long pentraxins, has been described to be associated with endothelial dysfunction in different cardiovascular disorders. No study has yet evaluated the possible direct effect of PTX3 on vascular function. METHODS AND RESULTS: Through in vitro experiments of vascular reactivity and ultrastructural analyses, we demonstrate that PTX3 induces dysfunction and morphological changes in the endothelial layer through a P-selectin/matrix metalloproteinase-1 pathway. The latter hampered the detachment of endothelial nitric oxide synthase from caveolin-1, leading to an impairment of nitric oxide signaling. In vivo studies showed that administering PTX3 to wild-type mice induced endothelial dysfunction and increased blood pressure, an effect absent in P-selectin-deficient mice. In isolated human umbilical vein endothelial cells, PTX3 significantly blunted nitric oxide production through the matrix metalloproteinase-1 pathway. Finally, using ELISA, we found that hypertensive patients (n=31) have higher plasma levels of PTX3 and its mediators P-selectin and matrix metalloproteinase-1 than normotensive subjects (n=21). CONCLUSIONS: Our data show for the first time a direct role of PTX3 on vascular function and blood pressure homeostasis, identifying the molecular mechanisms involved. The findings in humans suggest that PTX3, P-selectin, and matrix metalloproteinase-1 may be novel biomarkers that predict the onset of vascular dysfunction in hypertensive patients.
BACKGROUND:Pentraxin 3 (PTX3), the prototype of long pentraxins, has been described to be associated with endothelial dysfunction in different cardiovascular disorders. No study has yet evaluated the possible direct effect of PTX3 on vascular function. METHODS AND RESULTS: Through in vitro experiments of vascular reactivity and ultrastructural analyses, we demonstrate that PTX3 induces dysfunction and morphological changes in the endothelial layer through a P-selectin/matrix metalloproteinase-1 pathway. The latter hampered the detachment of endothelial nitric oxide synthase from caveolin-1, leading to an impairment of nitric oxide signaling. In vivo studies showed that administering PTX3 to wild-type mice induced endothelial dysfunction and increased blood pressure, an effect absent in P-selectin-deficient mice. In isolated human umbilical vein endothelial cells, PTX3 significantly blunted nitric oxide production through the matrix metalloproteinase-1 pathway. Finally, using ELISA, we found that hypertensivepatients (n=31) have higher plasma levels of PTX3 and its mediators P-selectin and matrix metalloproteinase-1 than normotensive subjects (n=21). CONCLUSIONS: Our data show for the first time a direct role of PTX3 on vascular function and blood pressure homeostasis, identifying the molecular mechanisms involved. The findings in humans suggest that PTX3, P-selectin, and matrix metalloproteinase-1 may be novel biomarkers that predict the onset of vascular dysfunction in hypertensivepatients.
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