Cardiomyocyte OCaR2 deficiency in catecholamine-induced cardiomyopathy drove severe remodeling, including a 3.7-fold cardiomyocyte reduction and myofibroblast expansion from 1% to 52%.
Does OCaR2 deficiency exacerbate cellular remodeling and pro-fibrotic macrophage expansion in a mouse model of catecholaminergic cardiomyopathy?
OCaR2 deficiency in cardiomyocytes exacerbates pathological remodeling, calcium overload susceptibility, and pro-fibrotic macrophage expansion in a mouse model of catecholaminergic cardiomyopathy.
Absolute Event Rate: 0% vs 0%
Abstract Background Catecholamine-induced cardiomyopathy encompasses life-threatening arrhythmogenic disorders triggered by sympathetic overdrive. While it is well established that calcium overload in cardiomyocytes (CMs) drives arrhythmogenesis, signalling mechanisms linking calcium overload to arrhythmias are mostly focused on aberrant calcium release from the sarcoplasmic reticulum. We identified OCaR2 as a novel regulator protein that critically determines Ca2+ release from endo-lysosomes in CMs. Its deletion potentiates catecholamine-evoked diastolic Ca2+ transients originating from endo-lysosomes triggering cardiac arrhythmias and maladaptive remodeling. Methods Experimental groups included cardiomyocyte-specific knock-out of OCaR2 (OCaR2 flox/flox; αMHC-Cre positive, termed OCaR2 cKO) and control (OCaR2 flox/flox; αMHC-Cre negative) mice receiving either saline or isoproterenol (ISO, 30mg/kg/day, 7 days) via osmotic minipumps. Single-nucleus RNA sequencing was performed using the 10x Chromium platform. Compositional changes were quantified using scCODA, and pseudobulk differential expression via DESeq2. Cell-cell communication was mapped using MultiNicheNet for ligand-receptor interactions. Results Hearts from ISO-treated OCaR2 cKO mice demonstrated profound cellular remodeling with 3.7-fold cardiomyocyte reduction (50% to 15%, inclusion probability=1) and dramatic macrophage expansion (8% to 30%, inclusion probability=0.78). A distinct CMs subpopulation emerged, characterized by marked upregulation of genes encoding determinants of CM calcium-handling: L-type channels (Cacna1d, logFC=3.25), T-type channels (Cacna1h, logFC=3.02; Cacna1g, logFC=2.41), store-operated calcium entry components (Stim1, logFC=1.68; Orai2, logFC=3.96), and sodium-calcium exchangers (Slc24a2, logFC=3.88; Slc8a3, logFC=2.73), indicating enhanced susceptibility to afterdepolarizations. Furthermore, these mice exhibited a significant expansion of Gpnmb+/Spp1+ macrophages expressing pro-fibrotic signatures. Cell-cell communication revealed bidirectional signaling: cardiomyocytes promoted anti-inflammatory macrophage polarization via Pros1-MerTK and ApoE-LRP1 interactions, while macrophages secreted pro-fibrotic mediators (TGF-β1, osteopontin, galectin-3), driving Postn+ myofibroblast expansion (1% to 52%, inclusion probability=1). Conclusions OCaR2 deficiency in cardiomyocytes leads to prominent reduction of CM proportions and extensive cardiac remodelling. A population of calcium-overload-prone cardiomyocytes emerged, potentially orchestrating maladaptive remodeling through apoptosis and pro-fibrotic immune cell recruitment. Our results suggest mechanistic links between dysregulation of Ca2+ release from endo-lysosomes and chronic remodeling in catecholaminergic cardiomyopathy. We are currently exploring whether OCaR2 dysregulation contributes to human catecholaminergic cardiomyopathy and represents a novel therapeutic avenue for preventing arrhythmias and cardiac fibrosis.
Gómez-ochoa et al. (Sun,) reported a other. Cardiomyocyte OCaR2 deficiency in catecholamine-induced cardiomyopathy drove severe remodeling, including a 3.7-fold cardiomyocyte reduction and myofibroblast expansion from 1% to 52%.