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 9

Cardiomyocyte-specific Shh deletion abolishes EPO-induced cardioprotection.

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Cardiomyocyte-specific Shh deletion abolishes EPO-induced cardioprotecti...
(A) Activation of Shh signaling after MI and EPO treatment. Hearts were treated with EPO or saline (control) and harvested 4 days (for Shh-N) or 7 days (for Patched) after MI (n = 4 for each). (B) Western blotting of Shh-N in the infarcted hearts from Shh-MerCre mice treated with or without tamoxifen. Mice were subjected to MI, treated with EPO, and sacrificed 4 days after MI (n = 4 for each condition). We measured LVEDD, FS, infarct size (C), the number of vessels, the ratio of vessels to cardiomyocyte, and the number of α-SMA–positive vessels (D) 14 days after MI (n = 8–14). *P < 0.05; #P < 0.01. (E and F) Western blotting of VEGF and qRT-PCR analysis of Ang-1 mRNA in the heart 7 days after MI. All mice were treated with EPO (n = 5). *P < 0.05. (G) Proposed mechanism underlying the cardioprotective effects of EPO during MI. The mechanisms denoted by the thicker lines are thought to be particularly important.