title: Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice.
abstract: Erythropoietin reportedly has beneficial effects on the heart after myocardial infarction, but the underlying mechanisms of these effects are unknown. We here demonstrate that sonic hedgehog is a critical mediator of erythropoietin-induced cardioprotection in mice. Treatment of mice with erythropoietin inhibited left ventricular remodeling and improved cardiac function after myocardial infarction, independent of erythropoiesis and the mobilization of bone marrow-derived cells. Erythropoietin prevented cardiomyocyte apoptosis and increased the number of capillaries and mature vessels in infarcted hearts by upregulating the expression of angiogenic cytokines such as VEGF and angiopoietin-1 in cardiomyocytes. Erythropoietin also increased the expression of sonic hedgehog in cardiomyocytes, and inhibition of sonic hedgehog signaling suppressed the erythropoietin-induced increase in angiogenic cytokine expression. Furthermore, the beneficial effects of erythropoietin on infarcted hearts were abolished by cardiomyocyte-specific deletion of sonic hedgehog. These results suggest that erythropoietin protects the heart after myocardial infarction by inducing angiogenesis through sonic hedgehog signaling.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ueda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takano
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Niitsuma
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Raita
authors.initials: R
authors.lastname: Uchiyama
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism / Q000494:pharmacology*; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
chemical_list: D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D016207:Cytokines; D053823:Hedgehog Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin