Suzanne M Eken1, Hong Jin1, Ekaterina Chernogubova1, Yuhuang Li1, Nancy Simon1, Changyan Sun1, Greg Korzunowicz1, Albert Busch1, Alexandra Bäcklund1, Cecilia Österholm1, Anton Razuvaev1, Thomas Renné1, Hans Henning Eckstein1, Jaroslav Pelisek1, Per Eriksson1, María González Díez1, Ljubica Perisic Matic1, Isabel N Schellinger1, Uwe Raaz1, Nicholas J Leeper1, Göran K Hansson1, Gabrielle Paulsson-Berne1, Ulf Hedin1, Lars Maegdefessel2. 1. From the Department of Medicine (S.M.E., H.J., E.C., Y.L., N.S., C.S., G.K., A.B., A.B., P.E., M.G.D., G.K.H., G.P.-B., L.M.) and Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (G.K., C.Ö., A.R., T.R., L.P.M., U.H.); Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL (C.Ö.); Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf, Germany (T.R.); Department of Vascular and Endovascular Surgery, Technical University Munich and DZHK Partner Site Munich, Germany (H.H.E., J.P., L.M.); Heart Center, Georg-August-University Göttingen, Germany (I.N.S., U.R.); and Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA (N.J.L.). 2. From the Department of Medicine (S.M.E., H.J., E.C., Y.L., N.S., C.S., G.K., A.B., A.B., P.E., M.G.D., G.K.H., G.P.-B., L.M.) and Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (G.K., C.Ö., A.R., T.R., L.P.M., U.H.); Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL (C.Ö.); Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf, Germany (T.R.); Department of Vascular and Endovascular Surgery, Technical University Munich and DZHK Partner Site Munich, Germany (H.H.E., J.P., L.M.); Heart Center, Georg-August-University Göttingen, Germany (I.N.S., U.R.); and Division of Cardiovascular Medicine, Stanford University, Palo Alto, CA (N.J.L.). lars.maegdefessel@tum.de.
Abstract
RATIONALE: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets. OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. METHODS AND RESULTS: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.
RATIONALE: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets. OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. METHODS AND RESULTS: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.
Authors: Hong Jin; Daniel Y Li; Ekaterina Chernogubova; Changyan Sun; Albert Busch; Suzanne M Eken; Peter Saliba-Gustafsson; Hanna Winter; Greg Winski; Uwe Raaz; Isabel N Schellinger; Nancy Simon; Renate Hegenloh; Ljubica Perisic Matic; Maja Jagodic; Ewa Ehrenborg; Jaroslav Pelisek; Hans-Henning Eckstein; Ulf Hedin; Alexandra Backlund; Lars Maegdefessel Journal: Mol Ther Date: 2018-01-31 Impact factor: 11.454
Authors: Daniel Y Li; Albert Busch; Hong Jin; Ekaterina Chernogubova; Jaroslav Pelisek; Joakim Karlsson; Bengt Sennblad; Shengliang Liu; Shen Lao; Patrick Hofmann; Alexandra Bäcklund; Suzanne M Eken; Joy Roy; Per Eriksson; Brian Dacken; Deepak Ramanujam; Anne Dueck; Stefan Engelhardt; Reinier A Boon; Hans-Henning Eckstein; Joshua M Spin; Philip S Tsao; Lars Maegdefessel Journal: Circulation Date: 2018-10-09 Impact factor: 29.690
Authors: Sébastien Foulquier; Evangelos P Daskalopoulos; Gentian Lluri; Kevin C M Hermans; Arjun Deb; W Matthijs Blankesteijn Journal: Pharmacol Rev Date: 2018-01 Impact factor: 25.468