ADENOSINE AND CA++ IN MYOCARDIAL PRECONDITIONING

Project: Research project

Project Details

Description

The overall goal of this application is to understand the subcellular
mechanisms of cardiac protection by calcium preconditioning against
calcium overload, which is commonly observed during post ischemic
reperfusion. The recently discovered phenomenon of Ca++ preconditioning
i.e. multiple l minute Ca++ depletion and 5 minutes Ca++ repletion,
confers strong protection if these hearts are subjected to the Ca++
overload or ischemia/reperfusion. The preliminary data suggest that the
reduction of cellular injury is mediated by adenosine and calcium
triggered mechanisms. The mechanisms underlying the unique protection by
Ca++ preconditioning remain to be elucidated.

The specific aims of this proposal are centered around three major
triggers of Ca++ preconditioning i.e. release of adenosine, catecholamine
and elevation of intracellular Ca++ and will address the following
questions. l) How does endogenous adenosine released during calcium
preconditioning protect the heart against severe Ca++ overload injury?
2) Does adenosine released during Ca++ preconditioning provide protection
as a result of its antiadrenergic effects? 3) Does catecholamine released
during Ca++ preconditioning protect against the Ca++ overload by
activating alpha1 adrenergic receptors? 4) Do adenosine and Ca++
elevation during Ca++ preconditioning activate K+ ATP channel? 5) Do Ca++
increase or other mediators released during Ca++ preconditioning activate
protein kinase C to provide protection via different intracellular
signaling pathways? 6) Do interventions that raise intracellular Ca++
mimic Ca++ preconditioning? 7) Can mild stress such as oxidants/oxygen
radicals induce protection similar to Ca++ preconditioning? 8) Finally,
does Ca++ preconditioning protect against the ischemia/reperfusion
injury?

The experimental protocols will use pharmacological approaches and
measurement of several different variables, e.g. measurement of
intracellular Ca++ in myocytes, cardiac function, nucleotides,
catecholamine and enzyme release, electron microscopy, immunolocalization
of protein kinase C isoforms, and other biochemical parameters of cell
injury. These studies will provide insights into the potential
involvement of adenosine and calcium-dependent pathways in the protection
of cell necrosis that typically occurs during Ca++ overload. This
investigation will have important implications for l) understanding
mechanisms of the cellular injury induced by Ca++ overload which occurs
in pathological conditions and 2) how the heart protects itself from Ca++
overload, 3) the designing of therapeutic interventions based on the
unique endogenous protection elicited by calcium preconditioning against
Ca+ + overload and ischemia/reperfusion injury in trauma patients or
during thrombolytic therapy, percutaneous transluminal angioplasty and
coronary bypass grafting.
StatusNot started