Deletion of Cd248 in Postn+ myofibroblast fails to attenuate pressure-overload induced cardiac remodeling and fibrosis in mice

Abstract Background Cardiac fibrosis, driven by activated Periostin (Postn)-expressing myofibroblasts, is a key pathophysiological feature of heart failure induced by pressure overload. The clinic trial tested tumor vascular regulator CD248 has been validated as a potential anti-fibrotic target in ischemic heart injury. We therefore tested the hypothesis that targeting Cd248 specifically in Postn + myofibroblasts ameliorates pressure-overload cardiomyopathy. Methods Single-cell RNA-sequencing data from murine hearts subjected to transverse aortic constriction (TAC) were analyzed to quantify the Cd248 + /Postn + fibroblast population. Subsequently, Postn + myofibroblast-specific inducible Cd248 knockout mice were subjected to TAC. Gene deletion was induced with tamoxifen from the day of surgery. Cardiac remodeling and function were analyzed 8 weeks after TAC. Results Analysis of scRNAseq data confirmed that about 1/3 of the fibroblasts in the 14-day TAC heart are Cd248 + Postn + fibroblasts. However, comprehensive echocardiographic analysis revealed no significant differences in key parameters of cardiac function or dimensions, including left ventricular ejection fraction, ventricular volumes, wall thickness and global muscle strain between PostnMCM + /-;Cd248fl/fl and PostnMCM + /- controls. Histological analysis at 8 weeks also showed no significant alteration in the extent of interstitial or perivascular fibrosis, myocardial vessel density, or cardiomyocyte hypertrophy. Conclusion The specific deletion of Cd248 in Postn -expressing myofibroblasts does not mitigate pathological remodeling or fibrosis in response to chronic pressure overload. These findings suggest the role of Cd248 in this cell lineage is not a primary driver of pressure-overload pathology. Therefore, a better understanding of the context-dependent functions of CD248 is critical to successfully guide the clinical translation of CD248-based anti-fibrotic therapies.