Heart failure remains the leading cause of death in the United States. It is impossible to develop a truly successful therapeutic strategy for patients with heart failure until we have a better understanding of the cellular and molecular events which are involved in the transition from stable, compensated cardiac hypertrophy to the downward spiral of heart failure. Several candidate pathways have been shown to mediate the compensated hypertrophy phase of cardiac remodeling. Among these is the JAK-STAT pathway, which is present in cardiac myocytes, is activated during hypertrophy, and can be shown to be stimulated in the heart by members of the IL6 cytokine family, as well as endothelin, angiotensin II, and mechanical stretch, all of which are potent stimuli during the transition to cardiac failure. Although studies in animal models have suggested that the JAK-STAT pathway may be involved in the compensated hypertrophy phase of cardiac remodeling, activation of the pathway has never been measured in an animal model of heart failure, or in the human failing heart. Preliminary data from our laboratory suggest that the JAK-STAT pathway is activated in the end-stage failing human heart, that it may be stimulated by angiotensin II, and that activation can be reversed when the failing human heart is mechanically unloaded. The presence of STAT dimers in the nuclei of failing human hearts suggests a role for this pathway in the altered transcriptional regulation associated with end-stage heart failure. We therefore hypothesize that angiotensin II-mediated activation of the JAK-STAT pathway is responsible for changes in cardiac muscle function and gene expression which occur in the transition from compensated hypertrophy to failure in the human heart, and that this pathway is inactivated during mechanical support of the failing human heart, leading to the """"""""reverse remodeling"""""""" which has been observed by our laboratory and others. We will test this hypothesis using a combination of human heart tissue studies and a mouse model of the transition from compensated left ventricular hypertrophy to heart failure. In the nonfailing human heart, the human heart with compensated left ventricular hypertrophy, the failing human heart, and the failing human heart which has been subjected to mechanical hemodynamic support, we will measure activation of the JAK-STAT pathway, markers of the heart failure phenotype, and the role of angiotensin II in mediating activation. In paired samples of tissue before and after mechanical unloading, we will use oligonucleotide microarray technology to identify genes which are regulated by unloading and which are potentially responsive to regulation by STAT transcription factors. In the mouse model of aortic banding, we will assess the changes in cardiac function and gene expression during the transition from hypertrophy to failure, define the relationship between these alterations and activation of the JAK-STAT pathway, and assess the role of angiotensin II in mediating the transition phase. This study will allow us to define the role and the timecourse of angiotensin II-mediated activation of the JAK-STAT pathway in human cardiac hypertrophy and heart failure. ? ?
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