The role of individual isoforms of p38 mitogen-activated protein kinase in myocardial infarction

Blockage of a coronary artery causes a heart attack. This decribes the symptoms caused by the death of the heart muscle downstream of the blockage. We are intersted in preventing the death of this muscle by studying the role of proteins known as p38 mitogen-activated protein kinases. These proteins aggravate muscle death and also cause on-going heart damage that can lead to heart failure.

Although there is general agreement that p38-Mitogen-Activated Protein Kinases (p38-MAPKs) play a crucial role in preconditioning, myocardial infarction and heart failure the contribution of individual p38 isoforms is either unknown or controversial. There are four p38-MAPK isoforms, alpha, beta, gamma and delta, and all have been reported to be expressed in the heart. However, the most commonly used readout of p38-MAPK activation, an immunoreactive dual phosphorylation motif within the activation loop, is common to all isotopes. Similarly, the pharmacological inhibitors used to infer involvement show poor selectivity for p38-MAPKs over other kinases or for one p38 MAPK isoform over another. The interpretation of any observations made with these inhibitors is further compounded by the fact that the alpha and beta isoforms, most sensitive to the commonly used pharmacological inhibitors, are thought to have opposing physiological roles. Finally, there is no small molecule that selectively inhibits either the gamma or delta isoforms. In combination these limitations have made it difficult to ascribe an observed physiological effect to a particular p38 isoform.
We propose to determine the contribution of individual p38 isoforms to preconditioning, myocardial infarction and post-infarction remodelling using our established murine models together with targeted mouse lines. The individual contribution of the beta, gamma and delta isoforms will be determined using the relevant ?knock out? line. The contribution of the alpha and beta isoforms will be determined using a chemical genetic approach utilising an allele-specific mutation that results in the substitution of a threonine residue critical to the binding of pharmacological inhibitors but not of ATP.
Our findings may lead to a greater understanding of the therapeutic benefits of ?blanket? p38-MAPK inhibition and to the substrates that mediate specific physiological effects. Such information may ultimately be used to avoid the toxicity that has curtailed a number of clinical trial programmes of p38 MAPK inhibition.