Project Summary/Abstract
Myocardial infarction (MI) is a major cause of death and disability worldwide, affecting >800,000
Americans annually. A delicate balance of repair and remodeling processes is required to preserve the structural
integrity and reinforce the injured myocardium following MI. Cardiac fibroblasts (CFs) are among the most
numerous cell types in the heart and play an essential role in fibrotic remodeling. Following ischemic injury,
surviving CFs exhibit a highly dynamic response involving the transition into an activated phenotype
characterized by increased proliferation, migration to the infarct region, and secretion of fibrotic proteins. Further,
CFs secrete a battery of paracrine signals to help coordinate the organ-level response to injury. Thus, proper
healing requires dynamic spatial and temporal control over CF function. Dysregulation of the CF response to
injury promotes pathological fibrosis, increased risk for arrhythmia, and cardiac dysfunction. While there have
been many studies exploring the diverse signaling cascades and stressors that cause CF activation, the precise
molecular pathways responsible for orchestrating dynamic changes in CF function across spatial and temporal
scales are not well understood.
Spectrin proteins are important for providing structural membrane support and spatiotemporal regulation
for cell signaling events. Recent work identified stress-induced loss of ßIV-spectrin, to be an important step in CF
activation and fibrosis. Further, loss of ßIV-spectrin was found to depend on Ca2+/calmodulin-dependent protein
kinase II (CaMKII). A broader role has been identified for ßIV-spectrin/CaMKII in regulating CF gene expression
through an interaction with signal transducer and activation of transcription 3 (STAT3), a signaling molecule and
transcription factor that promotes profibrotic mechanisms. Specifically, CaMKII is activated and promotes loss of
ßIV-spectrin and redistribution of STAT3 to the nucleus that lead to changes in fibrotic gene expression. Further,
we identified a molecular switch for ßIV-spectrin stability involving direct phosphorylation by calmodulin-
dependent protein kinase II (CaMKII). Together these data support our central hypothesis that ßIV-spectrin
coordinates a tunable network for temporal and spatial control of CF function and the normal healing process
following MI. These studies seek to offer new mechanistic insight into how the myocardial repair process is
orchestrated and to improve therapeutic options for patients who have experienced MI.
