Thursday, April 25, 2024
4/25/2024
ABSTRACT: Heart failure (HF) is a leading cause of death worldwide and defined by an inability of the heart to pump sufficient blood throughout the body. HF can be induced by persistent conditions such as high blood pressure, or by acute injuries such as myocardial infarction (MI). MI is characterized by the obstruction of a coronary blood vessel resulting in ischemia. Cardiomyocytes (CMs) affected by the ischemia undergo necrosis and apoptosis. To clear the resulting cellular debris, immune cells infiltrate the area while resident fibroblasts begin to secrete an extracellular matrix-rich scar to maintain the structural integrity of the heart. This eloquent response is essential to overcoming the initial injury, and exaggeration of any particular phase can have detrimental effects. While the etiology of disease associated with high blood pressure and MI are unique, they share similar features such as hypertrophy, inflammation, and fibrosis. To better understand the process of pathological cardiac remodeling, we performed RNA-sequencing to identify transcriptional gene expression profiles associated with pathologic fates. We identified a family of small proline-rich proteins (SPRRs) that are differentially regulated in disease; Sprr1a is highly upregulated in response to inflammatory cytokines in CFs and CMs in the border zone (BZ) after MI. Preliminary data suggests a predicted binding site between SPRR1A and tumor necrosis factor (TNF) receptor associated factor (TRAF)2, an E3 ubiquitin ligase that acts in response to the TNF receptor at the plasma membrane to propagate inflammatory signaling. Further investigation has led us to hypothesize that SPRR1A is altering the ubiquitination status or proteasome function in CMs to halt pro-inflammatory signaling and allow for the increase in inflammation-resolution pathways to occur. Separately, SPRR1A and TRAF2 may also be playing a role in the rate of cell survival along the border of injury. Understanding the coordination of the healing response following MI will build the basis needed for further therapeutic developments. This proposal aims to determine the novel in vitro mechanism of action and associated in vivo complications associated with the modulation of SPRR1A expression.
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