Caspase Recruitment Domain-Containing Protein 9 Knockout Rescues Heart Function by Reducing Fibrosis and Hypertrophy in a Pressure-Overload Model of Murine Heart Failure

Introduction: Nearly 1 in 3 adults aged over 20 in the US presents with hypertension, which can lead to left ventricular hypertrophy, hypertensive heart disease, and heart failure. The progressions of each are tied closely to elevated systemic and local inflammation. Caspase Recruitment Domain-containing Protein 9 (CARD9), a cytosolic protein expressed in macrophages and neutrophils, mediates secretion of inflammatory cytokines by these cells, which infiltrate the myocardium after injury and perpetuate a sustained inflammatory response. We recently reported rescued myocardial function by knockout of CARD9 (CARD9 -- ) in high-fat diet feeding. Macrophage deletion has been reported to ameliorate the progression of TAC-induced left ventricular hypertrophy and fibrosis. Combined, these findings suggest that CARD9 may be a valuable target in a TAC model of heart failure. Hypothesis: We hypothesized that knockout of CARD9 would rescue progression of TAC pressure-overload induced hypertrophy, fibrosis, and failure. Methods: C57BL/6 wild-type (WT) and CARD9 -- mice were assigned to thoracic aortic constriction (TAC) or to sham (CONT). To assess heart function, fractional shortening (FS), was measured by echocardiogram 1, 2, and 3 months post-surgery. Results: FS was compromised in WT-TAC compared to WT-CONT at 1 (35.2 vs. 47.8; p -- TAC at any time point. At 3 months, mice were sacrificed. Heart weight/tibia length was elevated in WT-TAC compared to WT-CONT (11.7 vs. 6.7; p -- TAC. Histological results of Masson’s trichrome stain suggested hypertrophy in both TAC groups, but revealed less fibrosis in CARD9 -- TAC than in WT-TAC. Conclusion: CARD9 is a novel target for TAC-induced cardiac dysfunction, at least in part through reductions in fibrosis and hypertrophy. Further study is needed to investigate signaling transduction involved, as well as the extent to which CARD9 -- may be protective in order to determine if it is a potential target for intervention in hypertensive heart disease.