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Early Erythropoietin Therapy Attenuates Remodeling and Preserves Function of Left Ventricle in Porcine Myocardial Infarction
  1. Sarah Chua, MD*†,
  2. Steve Leu, PhD*†,
  3. Yu-Chun Lin, PhD*†,
  4. Jiunn-Jye Sheu, MD,
  5. Cheuk-Kwan Sun, MD, PhD§,
  6. Sheng-Ying Chung, MD*,
  7. Han-Tan Chai, MD*,
  8. Fan-Yen Lee, MD,
  9. Ying-Hsien Kao, PhD,
  10. Chiung-Jen Wu, MD*,
  11. Li-Teh Chang, PhD,
  12. Sheung-Fat Ko, MD#,
  13. Hon-Kan Yip, MD*†
  1. From the *Division of Cardiology, Department of Internal Medicine, †Center for Translational Research in Biomedical Sciences, ‡Division of Thoracic and Cardiovascular Surgery, §Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC; ∥Department of Medical Research, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan, ROC; ¶Division of Basic Medical Science, Department of Nursing, Meiho University, Pingtung, Taiwan, ROC; and #Department of Radiology, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
  1. Received May 17, 2010, and in revised form November 21, 2010.
  2. Accepted for publication November 22, 2010.
  3. Reprints: Hon-Kan Yip, MD and Sheung-Fat Ko, MD, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Ta Pei Rd, Niao Sung Hsiang, Kaohsiung Hsien 83301, Taiwan. E-mail: han.gung{at}msa.hinet.net; sfatko{at}adm.cgmh.org.tw.
  4. Steve Leu and Sarah Chua contributed equally to this work.
  5. Sheung-Fat Ko contributed equally with Hon-Kan Yip.

Abstract

Erythropoietin (EPO) has been shown to have anti-inflammatory, antiapoptotic, and proangiogenic effects. This study investigated whether early EPO treatment effectively preserves left ventricular (LV) function in porcine acute myocardial infarction (AMI). Eighteen male mini-pigs divided into groups 1 (sham), 2 (AMI), and 3 (AMI with 2 consecutive EPO doses [7500 IU per animal each time] at 30 minutes and 24 hours after AMI induction) underwent echocardiography before and 14 days after AMI induction through left anterior descending artery (LAD) ligation with myocardium harvested for analysis. Larger infarcted areas (IA) were noted in group 2 than in group 3. In both IA and peri-IA, percentage of apoptotic nuclei and CD40-positive cells, messenger RNA expressions of IL-8, matrix metalloproteinase-9, caspase-3, and Bcl-2 associated x protein were highest, whereas proliferator-activated receptor-γ coactivator-1α, endothelial nitric oxide synthase and Bcl-2 were lowest in group 2. Oxidative stress and cytosolic cytochrome c in IA were increased (P < 0.001), whereas protein expression of connexin43, cytochrome c, and protein kinase C-ε in mitochondria were reduced in group 2 than in other groups (P < 0.045). The fibrosis in IA was notably decreased in group 3 compared with that in group 2. The number of small arterioles and capillary density in IA was highest in group 3, whereas LV performance was lowest in group 2 (P < 0.045). In conclusion, the results demonstrated that early EPO administration in a porcine AMI model effectively limits infarct size, attenuates LV remodeling, and preserves LV function.

Key Words
  • acute myocardial infarction
  • mini-pig model
  • erythropoietin
  • apoptosis
  • inflammation
  • mitochondrial damage
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