Widespread expression and release of enkephalins by non-neuronal tissues suggests enkephalins play an important role in remote preconditioning and cardioprotection.

Ischemic heart disease is a major contributor to death worldwide. Ischemic preconditioning (IPC) is a natural process that protects the heart from ischemic injury. The goal of our laboratory is to determine the mechanisms by which mediators of IPC exert their protective effects. Among the mediators of IPC are small opioid peptides called enkephalins. We found that numerous tissues, including skeletal muscle, express the precursor protein proenkephalin (PENK), and release enkephalins in a tissue-specific manner. We also found that exercise, which is potently cardioprotective, alters PENK levels in both heart and skeletal muscle, but not in intestine. Moreover, ischemia-induced enkephalin release is higher in hearts from exercised animals, as compared to control animals. Together, our data support a model wherein numerous non-neuronal tissues release enkephalins in response to ischemia and ischemic-like stresses (e.g., exercise). These enkephalins may then act locally or systemically to increase ischemic tolerance of the heart and other tissues. Our findings further suggest that enhancing or mimicking the protective effects of enkephalins may benefit patients with ischemic disease. [ABSTRACT FROM AUTHOR]