Heat shock proteins (HSP), also called stress proteins, are induced by specific types of stress including heat, and they are highly conserved from bacteria to man.1-4
The HSP70 family facilitates the folding of newly synthesized polypeptides in an adenosine triphosphate (ATP)-dependent manner, plays an important role in maintaining the dynamic stability of protein folding and protein-protein interactions within the cell, and inhibits protein aggregation. 5,6
These are referred to collectively as chaperone functions. By interacting with a range of cochaperones and client proteins, both constitutive and inducible HSPs regulate the functioning of other proteins and indeed whole signaling cascades. These interactions allow a cell to rapidly respond to stresses and changes in its environment without requiring protein synthesis, though induction of stress protein synthesis provides the next line of response. HSPs are divided into families on the basis of molecular weight. HSPs that are present as a single copy in bacteria (e.g., dna K), are generally represented by multiple related genes in eukaryotes (e.g., HSP70 family).
HSP70 family members have long been recognized to have cytoprotective effects. The human HSP70 family consists of at least 12 members.7
The best known members are the heat inducible form Hsp70/Hsp72, the constitutively expressed Hsc70/Hsp73/Hsc73, the endoplasmic reticulum form, Grp78/BiP, and Hsp75/mtHsp70/mortalin that is localized largely to mitochondria. Of these, the cytosolic inducible Hsp72 plays a major role in mediating cytoprotective, antiapoptotic, and immune regulatory effects, and is by far the best studied. Enhanced expression of Hsp72 in experimental models of stroke, sepsis, acute respiratory distress syndrome, renal failure, and myocardial ischemia, has been shown to reduce organ injury and in some cases improve survival.8-11
Deletion of the hsp70.1/3
gene is associated with poorer outcome in mice.12
In addition to their intracellular protective and antiapoptotic role, HSPs also function as extracellular signals.13
We will use HSP70 to refer to the entire family, and Hsp70 in instances where either Hsp72 or 73 is referred to, as some reports and some antibodies do not distinguish between these two cytosolic family members, though the majority of studies focus on the stress inducible Hsp72.
Clinical studies have begun to identify correlations between Hsp70 and outcome in a variety of diseases. A reduced ability to induce Hsp72 in peripheral lymphocytes was noted in patients with sepsis.14
Higher serum Hsp72 levels correlated with improved survival after trauma 15
and severe sepsis.16,17
Several studies have evaluated Hsp70 expression after myocardial infarction and cardiac surgery with bypass and found significant increases in Hsp70 expression in all cases.18-20
Thus increased levels of Hsp70 can indicate tissue damage, but they may also indicate the successful mounting of a stress response that correlates with tissue protection and better outcome.21
Hsp70 appears to participate in protection against organ dysfunction both in critically ill patients and in patients during the perioperative period. Overexpression by gene therapy or chemical induction of a stress response is under investigation as a potential treatment for ischemia in several organ systems, including the use of glutamine to increase Hsp70 in critically ill patients.17,22
We will focus primarily on data from cerebral ischemia in this review.