Background and Objective:
Cardiac fibrosis is a major pathological feature of heart disease and contributes significantly to the progression of heart failure, arrhythmias, and adverse cardiac remodeling. Excessive extracellular matrix deposition by activated cardiac fibroblasts increases myocardial stiffness and impairs cardiac function. Although calcium/calmodulin-dependent protein kinase II (CaMKII) is a well-established regulator of cardiomyocyte dysfunction and heart failure, its role in coordinating fibrotic remodeling and the downstream mediators involved remain incompletely understood.
Methods and Results:
Using a murine model of pressure overload, cardiomyocyte-specific deletion of CaMKIIδ and CaMKIIγ (DKO) significantly reduced interstitial and perivascular fibrosis, preserved systolic cardiac function, and attenuated the expression of profibrotic collagen genes. Transcriptomic analyses identified Angptl7 as one of the most strongly induced genes in response to cardiac stress, whereas its expression was markedly suppressed in CaMKII-deficient hearts.
Gain-of-function studies demonstrated that cardiomyocyte-specific overexpression of constitutively active CaMKII using adeno-associated virus (AAV9-CaMKIIδC) was sufficient to induce severe cardiac dysfunction, fibrosis, and activation of a heart failure gene program, accompanied by robust upregulation of Angptl7. In contrast, Angptl7 knockout (KO) mice were protected from CaMKII-induced systolic dysfunction. Mechanistic studies further revealed that CaMKII enhances Angptl7 expression and secretion and directly phosphorylates Angptl7, suggesting both transcriptional and post-translational regulation. Conditioned medium containing CaMKII-induced Angptl7 promoted collagen gene expression in induced pluripotent stem cell-derived cardiac fibroblasts, supporting a role for Angptl7 in mediating profibrotic signaling. Importantly, genetic deletion of Angptl7 protected mice from pressure overload-induced heart failure, resulting in improved survival, preserved cardiac function, and reduced fibrosis. These protective effects closely mirrored those observed in CaMKII-deficient mice, supporting a model in which Angptl7 functions downstream of CaMKII to drive extracellular matrix remodeling and cardiac dysfunction.
Conclusion:
Collectively, these findings identify a previously unrecognized CaMKII–Angptl7 signaling axis that promotes pathological cardiac fibrosis and heart failure progression. Targeting Angptl7 may represent a promising therapeutic strategy to interrupt CaMKII-driven fibrotic remodeling while preserving essential cardiac repair mechanisms, offering a novel approach for the treatment of chronic heart disease.
