Sonic hedgehog is a critical mediator of erythropoietin-induced cardiac protection in mice
Kazutaka Ueda, Hiroyuki Takano, Yuriko Niitsuma, Hiroshi Hasegawa, Raita Uchiyama, Toru Oka, Masaru Miyazaki, Haruaki Nakaya, Issei Komuro
Kazutaka Ueda, Hiroyuki Takano, Yuriko Niitsuma, Hiroshi Hasegawa, Raita Uchiyama, Toru Oka, Masaru Miyazaki, Haruaki Nakaya, Issei Komuro
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Research Article Cardiology

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

Kazutaka Ueda, Hiroyuki Takano, Yuriko Niitsuma, Hiroshi Hasegawa, Raita Uchiyama, Toru Oka, Masaru Miyazaki, Haruaki Nakaya, Issei Komuro

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Figure 2

Erythroid hematogenesis is not required for the protective effects of EPO, and EPO does not accelerate the cardiac homing of bone marrow–derived cells after MI.

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Erythroid hematogenesis is not required for the protective effects of EP...
WT and RES mice were subjected to MI and treated with EPO or saline (control). (A) Blood hemoglobin (Hb) levels 7 days after MI (n = 4). *P < 0.01. (B) Echocardiography and Masson trichrome staining were performed to analyze LV function and infarct size (n = 10). (C) Following MI and EPO treatment, the number of circulating CD34/Flk-1–double-positive EPCs increased in WT mice but not in RES mice. *P < 0.05 (n = 4). (D) Bone marrow cells from GFP-expressing mice were transplanted into WT mice. 7 and 14 days after MI, immunohistochemical staining for PECAM (red) was performed, and nuclei were counterstained with TO-PRO-3 (blue). GFP-positive cells (green) represent bone marrow–derived cells that moved into the heart and GFP/PECAM–double-positive cells denote bone marrow–derived endothelial cells. The numbers of GFP– and GFP/PECAM–double-positive cells in the border area (MI group) or LV free wall (sham group) were counted (n = 5–8). Scale bars: 50 μm. (E) WT bone marrow cells were transplanted (BMT) into RES mice, MI was induced, and the mice were treated with EPO or saline (control). FS, the number of vessels, and the ratio of vessels to cardiomyocytes in the border area are shown (n = 8).