Cardiomyocyte Specific Knock‐out of Erythropoietin Has Adaptive Non‐Erythropoietic Effects on Cardiac Function: A Novel Cardiac Myokine

Abstract

Introduction Erythropoietin (EPO), in response to hypoxia, is produced by the kidney, which stimulates erythropoiesis in the bone marrow. While the kidney is regarded as the primary source of EPO, mainly in vitro expression has been shown from cells or tissues of the brain, liver, and reproductive organs. However, whether these organs are an endogenous extra‐renal source and their physiological significance is unknown. Interestingly, recombinant human EPO (rhEPO) confers cardiac cytoprotection and increases contractility. Albeit, this occurs using supra‐physiological doses of rhEPO. Whether the kidney is responsible for these effects remains to be elucidated. Therefore, the primary objective of this research is to investigate the physiological relevance of endogenous cardiomyocyte EPO production. We hypothesized that: 1) adult cardiomyoctes are a source of EPO production and 2) the loss of cardiomyocyte EPO expression leads to a decrease in contractility and an increase in susceptibility to ischemia‐reperfusion injury. Methods Cardiomyocyte‐specific deletion of EPO (EPOfl/fl‐CM) was obtained by injecting 8‐week old α‐MHC‐MerCreMer+/−: EPO fl/fl male mice with 20 mg/kg tamoxifen daily for 5 days. Left ventricular (LV) EPO expression was determined using qPCR analysis. Cardiac structure and function were assessed by echocardiography, invasive hemodynamics and the Langendorff, respectively. Hematocrit was measured from blood collected via saphenous vein. Data was obtained 8‐weeks post‐tamoxifen. Results Paradoxically, EPOfl/fl‐CM mice exhibited a dramatic increase in whole heart EPO expression. Further, cardiac‐derived EPO confers inotropic, lusitropic and hypertrophic effects. Furthermore, in response to ischemia‐reperfusion injury, EPOfl/fl‐CM mice show profound cytoprotection. Importantly, we show that endogenous cardiac‐derived EPO is capable of improving cardiac function without affecting whole body Hct levels. Conclusion The knock‐out of EPO from the cardiomyocyte leads to a reciprocal increase in LV EPO expression, whereby an alternate cell in the heart is over‐compensating for the loss of cardiomyocyte‐derived EPO. This study furthers our fundamental understanding of EPO biology and establishes it as a novel cardiac myokine, capable of increasing cardiac function and driving hypertrophy. Support or Funding Information Heart and Stroke FoundationCanadian Institutes of Health Research