The cardiokine story unfolds: ischemic stress-induced protein secretion in the heart

Abstract

Intercellular communication depends on many factors, including proteins released via the classical or non-classical secretory pathways, many of which must be properly folded to be functional. Owing to their adverse effects on the secretion machinery, stresses such as ischemia can impair the folding of secreted proteins. Paradoxically, cells rely on secreted proteins to mount a response designed to resist stress-induced damage. This review examines this paradox using proteins secreted from the heart, cardiokines, as examples, and focuses on how the ischemic heart maintains or even increases the release of select cardiokines that regulate important cellular processes in the heart, including excitation-contraction coupling, hypertrophic growth, myocardial remodeling and stem cell function, in ways that moderate ischemic damage and enhance cardiac repair.

Figure 1. Cardiomyokines and Effects of Stress on Cardiomyokine Secretion

Panel A: By analogy to the release of adipokines from adipose tissue, and myokines from skeletal muscle tissue, the term, cardiomyokine, is used to describe proteins released by the heart that exert autocrine, paracrine and/or endocrine functions. Stress-induced cardiomyokines are a subset of cardiomyokines whose expression and secretion increase upon stresses that impair the release of other cardiomyokines. Panel B: No Stress- Stress-free conditions favors the synthesis of functional cardiomyokines involved in the maintenance of normal heart structure and function. Panel C: Ischemic Stress- During stress, such as sublethal ischemia, synthesis of non-functional cardiomyokines is moderated via cellular stress response machinery.

Figure 2. Classical and Nonclassical Secretory Pathways

Panel A: Classical Secretory Pathway- Stresses, such as sublethal ischemia, can induce cardiomyokine (CMK) genes, and in the case of the classical secretory pathway, those CMK mRNAs are translated on ER-associated ribosomes (1). The resulting proteins, depicted here in red (CMK-1), are initially localized to the ER lumen (Step 2), then transported in vesicles to the Golgi lumen (Step 3), after which they are released via secretory vesicle fusion with the plasma membrane (Step 4). Panel B: Nonclassical Secretory Pathway- Some transcripts encode CMKs that will be synthesized on cytosolic ribosomes (Step 1) and released via the nonclassical secretory pathway. The resulting proteins, depicted here in blue or green (CMK2, 3, 4 and 5) are destined for secretion via one of four nonclassical secretory pathways. Nonclassical CMK secretion takes place via vesicle-mediated (2-4), or non-vesicle-mediated pathways, as follows:

1. (2) endocytic secretory lysosomes (CMK-2),

2. (3) exosome-derived multivesicular bodies (CMK-3),

3. (4) microvesicles which are shed from the cell surface (CMK-4), and

4. (5) direct translocation of cytosolic proteins across the plasma membrane through complex protein conducting channels (CMK-5).

A portion of Panel B and the nomenclature used to describe the nonclassical secretory routes were inspired by a review written by Walter Nickel.