Heat shock proteins (HSPs) are induced in response to a variety of cellular stresses, and appear to be critical for maintaining cellular homeostasis. We and others have provided evidence that there is a general decline in stress-induced HSP expression during aging. Studies in this project are focused on examining HSP expression in a variety of physiologically relevant stress models, many of which involve complex regulatory mechanisms subject to alteration with aging. Efforts are directed at defining the physiologic and molecular events involved in controlling HSP expression in response to specific stresses, and determining the cause and significance of the age-related decline in the ability of animals to mount the response. Major areas of investigation over the past year have included: 1. Mechanism of HSP induction by acute hypertension. In previous studies we had demonstrated that acute hypertension leads to the induction of HSP70 in rat aorta. We have now completed studies demonstrating that this response is mediated through the heat shock transcription factor HSF1. 2. Vasopressin-induced HSP70 expression in the kidney. We have completed studies characterizing the induction of HSP70 in rat kidney by vasopressin; a response specific to renal tubule lining cells, and mediated via the V2 vasopressin receptor. 3. Potentiation of heat-induced HSP70 induction in the presence of aspirin. Recent studies in cultured cells have provided evidence that nonsteroidal antiinflammatory agents can potentiate the cellular response to heat stress by enhancing the DNA binding activity of HSF1. We have obtained preliminary evidence to suggest that we may be able to use this strategy to boost HSP70 expression in cells from aged rats. In addition, we have begun addressing whether this same phenomenon occurs in vivo, and have found that clinically relevant doses of aspirin do indeed lead to a potentiation of HSP70 mRNA induction during systemic heat stress. Further understanding of the underlying mechanisms contributing to this effect, could have direct therapeutic benefits.
