Project: Research project

Project Details


The induction of heat shock proteins during stress in part of the basic
biological response of cells to injury. Previous studies have suggested
that the 70 kDA heat shock protein (HSP 70) appears to protect cells
against injury by stabilizing the structure of macromolecules, as well
as by reactivating denatured proteins. Despite the recognized importance
of HSP 70 in a variety of biological model systems, the role of HSP 70
in the cardiac myocyte is unknown. Studies from our laboratory have shown
that brief ischemia in intact hearts resulted in an increase in HSP 70
mRNA, as well as in HSP 70 protein. These initial studies did not address
the important question of whether HSP 70 plays a protective role in
myocardial injury, or whether instead HSP 70 expression is simply a
nonspecific host response to tissue injury. Given the complexity of study
the role of HSP 70 in the intact heart, it has not been possible to
address this question in a simple experimental system. With the advent
of the AT-1 cardiac cell line, which can be passaged in culture, it is
now possible to selectively overexpress the HSP 70 gene in a simple
experimental system, and thereby isolate and examine the potential role
of HSP 70 in protecting the cardiac cell against injury. The purpose of the present application is to test the hypothesis that HSP
70 protects cultured cardiac cells against hypoxic injury. This will be
accomplished in three closely related specific aims. In Specific Aim 1,
we will overexpress the HSP 70 gene in cultured cardiac cells in the
presence and absence of hypoxia, in order to determine whether
overexpression HSP 70 is sufficient to protect cultured cardiac cells
against hypoxic injury. In Specific Aim 2, we will investigate whether
the protection of protein synthesis by HSP 70 following hypoxia (observed
in pilot experiments) is mediated through stabilization of ribosome
formation of protection of RNA synthesis. In Specific Aim 3, we will
extend the findings obtained in Specific Aim 1, by mutating known
functional domains of the HSP 70 protein, in order to determine how the
HSP 70 molecule protects the cardiac myocyte from hypoxia. The long term
objective of this research is to understand the function(s) of the heat
shock proteins and their role in the cardiac cell under normal conditions
and stress. This project will take an initial important first step toward
this goal by demonstrating in an extremely simple experimental system
that HSP 70 is capable and sufficient to protect cardiac cells from
hypoxic injury. The significance of this research is that elucidation of
the basic biological mechanisms whereby stress-response proteins are
protective may eventually lead to new insight into methods for myocardial
protection and preservation during ischemia, reperfusion, or following
coronary bypass surgery.
Effective start/end date7/1/945/31/99


  • National Institutes of Health
  • National Institutes of Health: $99,160.00
  • National Institutes of Health
  • National Institutes of Health: $82,205.00


  • Medicine(all)

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