Abstract Body: Background: Myocardial infarction (MI) has an estimated 30% one-year mortality rate, with over nine million Americans suffering from an infarct. A characteristic feature of an MI is the chronic loss of cardiomyocytes (CMs), exacerbated by their low proliferative capacity. As a result, repair of the infarct is dominated by a well-characterized immune response driving ventricular remodeling. Our group sought to understand if these rare cycling CMs played an important role in the myocardium’s response to ischemia/reperfusion (I/R) injury. As such, we developed a transgenic murine model to restrict Cre expression to adult CMs that reenter the cell cycle (DKRC) and, with RiboTag, performed RNA-seq of cycling versus non-cycling CMs after MI. We identified over 4000 genes differentially expressed. Growth differentiation factor 11 (GDF11), a secreted protein proposed to be anti-inflammatory, was upregulated 48-fold in cycling CMs after MI. This suggested an important and unique role of GDF11 secreted from cycling CMs.
Hypothesis: We hypothesized that cycling CMs secrete GDF11 to regulate the immune response after I/R by inhibiting pro-inflammatory polarization.
Methods/Results: We generated DKRC::GDF11^fl/fl (KO) mice to knock out GDF11 from adult cycling CMs. Wild-type Cre^- littermates were used as controls. GDF11 KO mice exhibited a decreased left ventricular ejection fraction 8 weeks post-I/R MI (KO: n=16, Cre^-: n=12; p<0.0001, 2-way ANOVA). Consistent with the functional decline, infarct size was significantly increased in the GDF11 KO cohort (n=9) compared to controls (n=6; p=0.04, two-tailed t-test). GDF11 KO mice (n=7) exhibited an increase in pro-inflammatory CCR2+ leukocytes seven days post-injury, suggesting cycling CM-immune crosstalk through GDF11 (n=13; p=0.01, two-tailed t-test). Flow cytometry is being conducted to further define this phenotype. Mice in this cohort showed about 2-fold increase in cycling CMs compared to controls (p=0.03, two-tailed t-test). This trend continues by 8 weeks post-MI, with GDF11 KO mice (n=10) exhibiting a striking 15-fold increase in cycling (n=13; p=0.0002, 2-tailed t-test).
Conclusions: Our results suggest that GDF11 secreted from cycling CMs after MI modulates inflammatory leukocyte recruitment, which in turn may influence additional cycling events. Additional experiments are being conducted to define the relationship between cycling CM-GDF11 and the immune response and the impact of GDF11 itself on CM cycling.