Ischemic preconditioning activates prosurvival kinases and reduces myocardial apoptosis

Chang-Chi Lai; Chia-Yu Tang; Shu-Chiung Chiang; Kuo-Wei Tseng; Cheng-Hsiung Huang

doi:10.1016/j.jcma.2015.04.006

Ischemic preconditioning activates prosurvival kinases and reduces myocardial apoptosis

J Chin Med Assoc. 2015 Aug;78(8):460-8. doi: 10.1016/j.jcma.2015.04.006. Epub 2015 Jun 10.

Authors

Chang-Chi Lai¹, Chia-Yu Tang², Shu-Chiung Chiang³, Kuo-Wei Tseng⁴, Cheng-Hsiung Huang⁵

Affiliations

¹ Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Department of Exercise and Health Sciences, University of Taipei, Taipei, Taiwan, ROC.
² Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
³ Institute of Hospital and Health Care Administration, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
⁴ Department of Exercise and Health Sciences, University of Taipei, Taipei, Taiwan, ROC.
⁵ Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. Electronic address: chhuang@vghtpe.gov.tw.

PMID: 26071976
DOI: 10.1016/j.jcma.2015.04.006

Abstract

Background: Ischemic preconditioning has been reported to protect the myocardium against ischemia and reperfusion injury. The underlying mechanisms have been extensively investigated but are not fully elucidated. In this study, we investigated the role of apoptosis in ischemic preconditioning protection and the signal pathways involved.

Methods: Myocardial ischemia and reperfusion were induced in anesthetized male Sprague-Dawley rats by a 40-minute occlusion and a 3-hour reperfusion of the left anterior descending coronary artery. Ischemic preconditioning was elicited by two 10-minute coronary artery occlusions and two 10-minute reperfusions.

Results: The myocardial infarct size, expressed as the percentage of area at risk, was significantly decreased in the ischemic preconditioning group (16.8 ± 2.0% and 27.9 ± 2.7% in the ischemia and reperfusion groups, respectively, p < 0.001). Additionally, ischemic preconditioning significantly reduced apoptosis, as evidenced by the decrease in the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei, DNA laddering, and caspase-3 activation. Western blot analysis revealed that ischemic preconditioning significantly reduced myocardial tumor necrosis factor-α levels. Bcl-2 was increased, whereas Bax was decreased in the myocardium. Phosphorylation of the prosurvival kinases, including Akt and extracellular signal-regulated kinases 1 and 2, was significantly increased. Hemodynamics, area at risk, and mortality did not differ significantly among the groups.

Conclusion: Ischemic preconditioning reduces apoptosis induced by myocardial ischemia and reperfusion. The underlying mechanisms might be related to inhibition of both the extrinsic and the intrinsic apoptotic pathway via inhibition of production of tumor necrosis factor-α, modulation of expression of Bcl-2 and Bax, and activation of the prosurvival kinases.

Keywords: apoptosis; ischemia and reperfusion injury; ischemic preconditioning; myocardial infarction; prosurvival kinases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Extracellular Signal-Regulated MAP Kinases / metabolism*
Hemodynamics
In Situ Nick-End Labeling
Ischemic Preconditioning, Myocardial*
Male
Myocardium / pathology*
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism*
Rats
Rats, Sprague-Dawley
Signal Transduction / physiology
Tumor Necrosis Factor-alpha / biosynthesis

Substances

Tumor Necrosis Factor-alpha
Proto-Oncogene Proteins c-akt
Extracellular Signal-Regulated MAP Kinases