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 MI is the chronic loss of cardiomyocytes (CMs), exacerbated by their low proliferative capacity. We developed a transgenic murine model to restrict Cre expression to adult CMs that reenter the cell cycle (DKRC) and, with RiboTag, we performed RNA-seq of cycling CMs versus non-cycling CMs after MI. We identified a striking variation between the two populations, with over 4000 genes differentially expressed. Growth differentiation factor 11 (GDF11), a protein of interest in the cardiovascular field, was upregulated 48-fold in cycling CMs after MI.
Hypothesis: We hypothesized that cycling CMs secrete mature GDF11 to prevent further entry or re-entrance into the cell cycle as a means to inhibit sarcomere dissolution and loss of contractile elements.
Methods/Results: We generated DKRC::GDF11^flox/flox mice to knock out GDF11 from adult cycling cells. MI I/R surgeries were performed, and left ventricular ejection fraction (LVEF) was measured by echocardiogram at 2, 4, 6, and 8 weeks after MI. Immunohistochemistry (IHC) was conducted 8 weeks after MI. The LVEF was significantly decreased at all time points after MI in GDF11 KO mice (male n = 7, female n = 3) compared to Cre^- controls in both sexes (male n = 8, female n = 4; p < 0.0001, 2-way ANOVA). Infarct scar was significantly increased in the GDF11 KO cohort (n = 8) compared to Cre^- controls (n = 9; p = 0.03, two-tailed t-test). Surprisingly, GDF11 KO mice had significant increases in proliferating CMs after MI. GDF11 KO mice (n = 8) had 150 42 cycled cells, compared to 11 2 cycled cells in aDKRC controls (n = 10; p = 0.002, 2-tailed t-test). Sarcomere structure in cycling cells (n = 89) is irregular when compared to non-cycling cells (n = 83), suggesting dissolution of contractile elements (p < 0.0001, 2-tailed t-test).
Conclusions: Our results suggest that GDF11 secreted from cycling cells after MI may prevent subsequent CM cycling. Interestingly, this correlates with a decreased LVEF, suggesting the cell-cycle-associated sarcomere disassembly may negatively impact ventricular function.