Fibroblast Has2 limits acute heart failure following myocardial infarction in male mice

Changes to the extracellular matrix support acute wound healing following myocardial infarction. Fibroblasts regulate the composition of the extracellular matrix, in part, by secreting hyaluronan. Details surrounding the regulation, source, and impact of hyaluronan production after MI are largely unknown. We recently showed that activated fibroblasts produce hyaluronan via Has2; however, the extent to which this function impacts acute ventricular remodeling following myocardial infarction (MI) has not been tested. Hence, the goal of the present study was to elucidate the impact of fibroblast-borne Has2 expression in acute ventricular remodeling. Adult, male and female mice were subjected to non-reperfused myocardial infarction and followed for 1 week and subjected to echocardiography and hearts were harvested for pathology and biochemical analyses. Mice were deficient in fibroblast-derived Has2 (Has2^-/-) or were littermate controls that were sufficient in fibroblast Has2. At 1-week post-MI, Has2^-/- male mice had exacerbated heart failure reflected by lower cardiac output due to lower stroke volume, when compared to littermate males. The genotype effect was not evident in female mice. To assess potential mechanisms, we examined hearts for fibrosis, cardiomyocyte cross-sectional area, and capillary density; there were no significant differences in any of these endpoints. Deletion of Has2 also did not impact collagen organization, which could have indicated changes in ventricular stiffness. Fibroblast-derived Has2 supports cardiac function early after MI. The mechanism responsible for this and why it is not evident in female mice is unclear.