Inhibition of 14q32 MicroRNAs miR-329, miR-487b, miR-494, and miR-495 increases neovascularization and blood flow recovery after ischemia.

Autor:	Welten SM; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., Bastiaansen AJ; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., de Jong RC; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., de Vries MR; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., Peters EA; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., Boonstra MC; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., Sheikh SP; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., La Monica N; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., Kandimalla ER; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., Quax PH; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.)., Nossent AY; From the Department of Surgery (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., M.C.B., P.H.A.Q., A.Y.N.) and Einthoven Laboratory for Experimental Vascular Medicine (S.M.J.W., A.J.N.M.B., R.C.M.d.J., M.R.d.V., E.A.B.P., P.H.A.Q., A.Y.N.), Leiden University Medical Center, Leiden, The Netherlands; Department of Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark (S.P.S.); and Idera Pharmaceuticals, Cambridge, MA (N.L.M., E.R.K.). a.y.nossent@lumc.nl.
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2014 Sep 26; Vol. 115 (8), pp. 696-708. Date of Electronic Publication: 2014 Aug 01.
DOI:	10.1161/CIRCRESAHA.114.304747
Abstrakt:	Rationale: Effective neovascularization is crucial for recovery after cardiovascular events. Objective: Because microRNAs regulate expression of up to several hundred target genes, we set out to identify microRNAs that target genes in all pathways of the multifactorial neovascularization process. Using www.targetscan.org, we performed a reverse target prediction analysis on a set of 197 genes involved in neovascularization. We found enrichment of binding sites for 27 microRNAs in a single microRNA gene cluster. Microarray analyses showed upregulation of 14q32 microRNAs during neovascularization in mice after single femoral artery ligation. Methods and Results: Gene silencing oligonucleotides (GSOs) were used to inhibit 4 14q32 microRNAs, miR-329, miR-487b, miR-494, and miR-495, 1 day before double femoral artery ligation. Blood flow recovery was followed by laser Doppler perfusion imaging. All 4 GSOs clearly improved blood flow recovery after ischemia. Mice treated with GSO-495 or GSO-329 showed increased perfusion already after 3 days (30% perfusion versus 15% in control), and those treated with GSO-329 showed a full recovery of perfusion after 7 days (versus 60% in control). Increased collateral artery diameters (arteriogenesis) were observed in adductor muscles of GSO-treated mice, as well as increased capillary densities (angiogenesis) in the ischemic soleus muscle. In vitro, treatment with GSOs led to increased sprout formation and increased arterial endothelial cell proliferation, as well as to increased arterial myofibroblast proliferation. Conclusions: The 14q32 microRNA gene cluster is highly involved in neovascularization. Inhibition of 14q32 microRNAs miR-329, miR-487b, miR-494, and miR-495 provides a promising tool for future therapeutic neovascularization. (© 2014 American Heart Association, Inc.)
Databáze:	MEDLINE
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