Role of Activin Type II receptor signaling in age-related heart failure

Project Summary/Abstract Heart failure (HF) is a major cause of morbidity and mortality in older adults, and currently representsthe leading cause of hospitalization in the elderly. Advanced age is one of the strongest risk factors for HF,although why this is the case and whether it is possible to intervene in this process, remain unclear. In thiscontext, the role of Activin type II receptor (ActRII) ligands - and their potential catabolic effects in aging anddisease - has been a subject of intense interest and controversy in HF. There is a fundamental gap in ourunderstanding of how aging contributes to HF. Our over-arching hypothesis is that ActRII activation increaseswith age as well as biomechanical cardiac stress, and contributes to cardiac dysfunction in multiple forms ofage-related HF. Our long-term goal is to understand the mechanisms linking ActRII signaling to cardiacdysfunction and learn whether these pathways can be targeted for therapeutic benefit. The objective of thecurrent application is to examine the functional contribution of ActRII signaling in multiple age-related modelsof HF, and to elucidate the underlying mechanisms. Our preliminary data suggest that activity of the ActRIIpathway increases with age, frailty, and HF in human cohorts, and with age and HF in mice. The increasedactivity appears driven predominantly by Activin-A rather than other ligands. In mice, elevating Activin-Alevels was sufficient to cause cardiac dysfunction, while inhibition of the pathway in three distinct HF modelsprevented or reversed HF. The translational importance of these findings is underscored by the existence ofpathway inhibitors currently in trials for other indications. The proposed work will be pursued in threeintegrated Specific Aims. In Aim 1, we will use specific and effective gain- and loss-of-function models todirectly assess the role of ActRII signaling in HF, and to examine the role of ActRII in cardiomyocytes in vivo.In Aim 2, we will elucidate the mechanism(s) by which ActRII leads to cardiac dysfunction. In Aim 3, we willinvestigate the dynamic regulation of this pathway in biobanked samples from elderly patients with heartfailure using targeted mass spectrometry assays in collaboration with Dr. Steven Carr, Director of Proteomicsat the Broad Institute. The functional importance of correlative clinical data will be examined using in vivomodels, which will be supported by in vitro investigation of primary cardiomyocytes to elucidate the underlyingmechanisms. Our approach combines innovative hypotheses, technologies, unique animal models, andtranslational work in relevant clinical populations with the complementary expertise of an outstanding teamof collaborating investigators. The proposed research is significant, because it is expected to advance ourunderstanding of age-related HF and delineate pathways relevant to aging and disease with the potential tomitigate these clinically important conditions.