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Ann Thorac Surg 1999;68:628
© 1999 The Society of Thoracic Surgeons
a PO Box 1139, Melrose, MA 02176 USA
To the Editor
Gowda and coworkers [1] have provided further insights into our understanding of the pathophysiology of global cardiac ischemia. However, two observations need to be considered.
First, heat shock proteins or chaperones [2] are the only component of several signaling proteins that are activated after pathologic conditions such as ischemia, hyperthermia, or cardiac bypass. In particular, an inflammatory regulator NF-
B, which designates a nuclear transcription factor of the immunoglobulin light-chain gene, first identified in murine B-lymphocytes, is concurrently stimulated by oxidants or inflammatory noxious stimuli and is normally inhibited (sequestered in an inactive form in the cytoplasm of most mammalian cells) by a protein called IKB [3]. Interestingly, NF-B has been shown to have pleiotropic roles and to regulate among others, nitric oxide synthase and cyclo-oxygenase, triggers the complement cascades, and activates tumor necrosis factor-
[4], all of which are far more potent biomolecular signals with known deleterious effects on the cell as compared to the salutary effects of heat shock proteins or the enzyme catalase.
Moreover, unlike heat shock proteins, which are expressed in mere hours, the induction and the feedback amplification that sustains the NF-B response can take a day or more [4]. As a consequence, these facts suggest that the duration and amplitude of cytoprotection against ischemic alterations or of the more critical "recovery time," reflect the final balance between both mediators: the heat shock protein and the NF-B complex [5]. Therefore, maintenance of functional recovery in the heat-shocked rats reported in these experiments beyond 24 hours is questionable and needs to be established. Unquestionably, what controls the attenuation of ischemia and inflammation is as complex and stringent as those factors that perpetuated them in the first place, and "the plot thickens."
Therefore, the investigators of the current study should focus on trying to understand how these different and complex transduction signals interact. As a testimony to the highly conserved and interacting activities of these regulatory peptides, the group of genes encoding NF-B, IKB, tumor necrosis factor-, and heat shock proteins are remarkably concentrated in a specific cluster to be designated as the major histocompatibility class IV [6].
Second, as the process of protein degradation is still the subject of intense research [7], it is worth noting that changes of ubiquitin–proteasome-dependent (ie, nonlysosomal) proteolysis has as much a critical influence on the control of cellular well being and of stress recovery [8] as that of particular regulatory protein biosynthesis (eg, the rate of synthesis of new chaperones referenced in the article). Therefore, the inextricable role of protein destruction in the development of tolerance to ischemic damage is paramount and continuing to emerge.
In conclusion, only in this context do we trust that chaperones will inevitably have an impact on future therapeutic applications of major clinical relevance as was aptly anticipated by the researchers.
References
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