Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice.
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.
Ueda
Kazutaka
K
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan.
Takano
Hiroyuki
H
Niitsuma
Yuriko
Y
Hasegawa
Hiroshi
H
Uchiyama
Raita
R
Oka
Toru
T
Miyazaki
Masaru
M
Nakaya
Haruaki
H
Komuro
Issei
I
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
D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D016207:Cytokines; D053823:Hedgehog Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin