The adult heart is a dynamic organ capable of remodeling its architecture and size in response to changing workloads or pathologic insults. The heart senses developmental, physiological, and pathological stimuli through membrane bound receptors or internal stretch receptors that initiate signal transduction cascades. These intracellular signaling events not only control moment-to-moment alterations of intracellular physiology, but they also reprogram gene expression within cardiac myocytes permitting permanent adaptive changes in myocyte biology. The mitogen-activated protein kinases (MAPK) are a series of successively acting kinases that mediate diverse biologic responses in all eukaryotic cells. The p38 MAPK branch of the MAPK cascade is thought to play an important role in transducing the cardiac hypertrophic response and to regulate cardiomyocyte apoptosis following ischemic damage. While a great deal of investigation has been conducted in cultured neonatal cardiomyocytes concerning a role for p38 MAPK, very little investigation has been extended to the intact heart. Preliminary data from the sponsor's laboratory suggests that p38 signaling actually antagonizes the cardiac hypertrophic response of the adult heart. This application will test the hypothesis that p38 MAPK signaling negatively regulates the cardiac hypertrophic response by directly effecting another signaling pathway (calcineurin-NFAT). We will also investigate the hypothesis that p38 MAPK signaling is pro-apoptotic following ischemic insults to the adult heart. Collectively, multiple transgenic mouse models have been generated to examine the role of p38 in pathological responses of the adult heart.
| Kaiser, Robert A; Liang, Qiangrong; Bueno, Orlando et al. (2005) Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemia-reperfusion-induced cell death in vivo. J Biol Chem 280:32602-8 |
| Kaiser, Robert A; Lyons, Jefferson M; Duffy, Jodie Y et al. (2005) Inhibition of p38 reduces myocardial infarction injury in the mouse but not pig after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 289:H2747-51 |
| Kaiser, Robert A; Bueno, Orlando F; Lips, Daniel J et al. (2004) Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J Biol Chem 279:15524-30 |
