Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice

• Published in: The Journal of clinical investigation Vol. 120; no. 6; pp. 2016 - 2029
• Main Authors: Ueda, Kazutaka, Takano, Hiroyuki, Niitsuma, Yuriko, Hasegawa, Hiroshi, Uchiyama, Raita, Oka, Toru, Miyazaki, Masaru, Nakaya, Haruaki, Komuro, Issei
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2010
• Subjects: Angiogenesis; Angiogenesis Inducing Agents - metabolism; Angiogenesis Inducing Agents - pharmacology; Angiopoietin-1 - genetics; Angiopoietin-1 - metabolism; Angiopoietin-1 - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biomedical research; Bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Cells - physiology; Capillaries - metabolism; Capillaries - physiopathology; Cardiac function; Cardiomyocytes; Complications and side effects; Cytokines; Cytokines - genetics; Cytokines - metabolism; Cytokines - pharmacology; Erythropoietin; Erythropoietin - genetics; Erythropoietin - metabolism; Erythropoietin - pharmacology; Gene expression; Genetic aspects; Heart attack; Heart attacks; Heart failure; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Physiological aspects; Prevention; Properties; Recombinant Proteins; Risk factors; Signal Transduction - drug effects; Signal Transduction - genetics; Sonic hedgehog; Up-Regulation - drug effects; Ventricular Remodeling - drug effects; Ventricular Remodeling - genetics; Ventricular Remodeling - physiology; Japan
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci39896

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.