Rapamycin treatment of healthy pigs subjected to acute myocardial ischemia-reperfusion injury attenuates cardiac functions and increases myocardial necrosis.

Abstract

BACKGROUND:

The mammalian target of rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplantation. However, it has other nonimmune functions: in the cardiovascular system, it is a regulator of heart hypertrophy and locally, in coated vascular stents, it inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism, and survival, we hypothesized that inhibiting it with rapamycin before an acute myocardial ischemia-reperfusion injury (IRI) would confer cardioprotection by virtue of slowing down cardiac function and metabolism.

METHODS:

Yorkshire pigs received either placebo or 4 mg/d rapamycin orally for 7 days before the IRI. All animals underwent median sternotomy, and the mid-left anterior descending coronary artery was occluded for 60 minutes followed by 120 minutes of reperfusion. Left ventricular pressure-volume data were collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively, and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by Western blotting with specific antibodies against mTOR substrates phosphorylating sites.

RESULTS:

Rapamycin before treatment impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities.

CONCLUSIONS:

Acute myocardial IRI, in healthy pigs treated with rapamycin, is associated with decreased cardiac function and higher myocardial necrosis.

• Authors: Antonio D Lassaletta, Nassrene Y Elmadhun, Arthus V D Zanetti, Jun Feng, Javier Anduaga, Reginald Y Gohh, Frank W Sellke, Cesario Bianchi
• Journal: The Annals of thoracic surgery (Ann Thorac Surg) Vol. 97 Issue 3 Pg. 901-7 (Mar 2014) ISSN: 1552-6259 [Electronic] Netherlands
• PMID: 24266948 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Chemical References

• Immunosuppressive Agents
• Sirolimus

Topics

• Acute Disease
• Animals
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Male
• Myocardial Reperfusion Injury (drug therapy, physiopathology)
• Myocardium (pathology)
• Necrosis (chemically induced)
• Sirolimus (adverse effects, therapeutic use)
• Swine