Why the study?
Does fibroblast-specific Has2 deletion alter acute ventricular remodeling and immune response following myocardial infarction in mice?
Does fibroblast-specific Has2 deletion alter acute ventricular remodeling and immune response following myocardial infarction in mice?
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Fibroblast-derived hyaluronan appears to exert a beneficial effect on cardiac function following myocardial infarction, with notable sex-specific differences in functional and immune responses.
Background: Following myocardial infarction (MI), the extracellular matrix (ECM) component hyaluronan (HA) accumulates. Our recent work shows that Has2 expression in fibroblasts drives accumulation of HA. The role of HA following MI is largely unknown. Goal: To determine the role of fibroblast derived HA in acute ventricular remodeling. Methods and Results: A tamoxifen-inducible, fibroblast-specific (fb) deletion model was used to decrease Has2 (major HA synthesizing enzyme) expression in mice. Following recombination, mice were subjected to non-reperfused MI and tissue was collected 7 days later. Echocardiography showed a significant reduction in stroke volume (n=17 per group, p=0.0136) and cardiac output (n=17 per group, p=0.0082) in male fb Has2 -/- samples, while no significant changes were observed in females. Blood, bone marrow, and spleens from wild-type and fb Has2 -/- mice were analyzed using flow cytometry to assess changes in immune cell populations. No significant changes were seen in the number bone marrow cells per tibia (n>/=15 per group, per sex), the cell count per mg of spleen tissue, or the size of the spleen (n>/=9 per group, per sex). Yet, there was a significant increase in the number of cells per mL in female peripheral blood samples (p=0.0381, n>/=15 per group) compared to wild-type controls. No significant changes were observed in the number of monocytes (Cd11b + Ly6G - CD115 + ), neutrophils (Cd11b + Ly6G + ), T cells (CD3 + B220 - ), or B cells (B220 + CD3 - ) in bone marrow and spleen samples; however, there was a significant increase in circulating neutrophils (p=0.0493, n>/=15 per group) and T cells (p=0.0067, n>/=15 per group) in the female fb Has2 -/- mice. This change was not observed in the male samples. Conclusion: Fibroblast specific Has2 deletion prior to MI reduced cardiac function in males. There was no impact on immune cell populations in the bone marrow or spleen; however, the number of circulating neutrophils and T cells was significantly increased in female fb Has2 -/- mice. Overall, impaired indices of cardiac function indicate that accumulating hyaluronan exerts benefit following MI.
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Howard et al. (2025) studied Myocardial infarction. Fibroblast-specific Has2 deletion vs. Wild-type controls was evaluated on Stroke volume (p=0.0136).
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