Deletion of Cd248 in Postn positive myofibroblast Fails to Attenuate Cardiac Remodeling and Fibrosis in a Murine Model of Pressure-Overload Cardiomyopathy

BackgroundCardiac 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. MethodsSingle-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. ResultsAnalysis 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. ConclusionThe 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.