Methods for preventing or reducing ischemia/reperfusion induced myocardial cell death

Boston Biomedical Research Institute
posted on 05/12/2011

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Background: PUMA (p53 upregulated modulator of apoptosis) encodes a BH3-only proapoptotic Bcl-2 family protein that is involved in p53-dependent as well as independent apoptosis.
Given the requirement for PUMA to integrate and implement a number of diverse cell death signals, we assessed the role of PUMA in cardiac ischemia/reperfusion injury by generating PUMA knockout mice.
Targeted deletion of PUMA led to inhibition of ischemia/reperfusion-induced apoptosis and necrosis, reduced infarct size and significantly better functional recovery in an ex vivo isolated Langendorff heart perfusion model.
We have also shown that upon activation PUMA undergoes phosphorylation-dependent dimerization that is induced by ischemia/reperfusion.
Application: Our findings establish PUMA as a critical mediator of cardiomyocyte death in response to ischemia/reperfusion and recommend the PUMA gene as a primary target for therapeutic intervention for several reasons.
First, PUMA deletion is more effective than similar strategies used in studies of others, such as Bax-deficiency and Bcl-2 or Bcl-xL overexpression.
Second, the effect of PUMA is specific for cell death, while other potentially useful target proteins also present activities not related to cell death providing a potential source of side effects.
Third, the phosphorylation-dependent dimerization of PUMA provides an excellent target for drug discovery.
Downregulation of PUMA in cardiac myocytes during infarction could therefore be achieved by using drugs, by adenoviral delivery of peptide inhibitors or by any other methods.
In addition, stem cells used in cardiac cell therapy approaches could also be improved by making them resistant against apoptosis and necrosis by downregulating their PUMA level/activity.
Status: US. patent application filed April, 2004