Abstract 19631: Scleraxis Regulates Pressure Overload-Induced Cardiac Fibrosis

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Introduction: Cardiac fibrosis is an independent risk factor for heart failure and death that currently lacks any specific treatment. Fibrosis is the uncontrolled synthesis of matrix components such as collagen and fibronectin, elevating myocardial wall stiffness, decreasing compliance, increasing arrhythmogenesis, and contributing to heart failure. Proliferation and phenotype conversion of fibroblasts to myofibroblasts contributes critically to the progression of fibrosis. Restricting the activation of myofibroblasts could thus be beneficial for restoring the function of the fibrotic heart. Our previous studies have shown that the transcription factor scleraxis governs the production of major matrix proteins including collagen, α-smooth muscle actin and fibronectin, and regulates fibroblast to myofibroblast phenoconversion. Scleraxis knockout animals exhibit a 50% reduction in the resident cardiac fibroblast population and decreased basal extracellular matrix production, but the role of scleraxis in cardiac fibrosis is unclear.

Hypothesis: Gene deletion of scleraxis will attenuate pressure overload-induced cardiac fibrosis.

Methods: We performed ubiquitous (pan-Cre) or cardiac fibroblast-specific (Tcf21-iCre) inducible deletion of the floxed scleraxis gene via administration of tamoxifen to adult mice to activate Cre. At 8 weeks of age, pressure overload was surgically induced in wild-type (WT) and scleraxis conditional null mice by transverse aortic constriction (TAC; n=10). Sham-operated animals served as the control (n=10). Animals were sacrificed at 4 or 8 weeks post-surgery and analyzed for cardiac fibrosis and function.

Results: Deletion of scleraxis significantly reduced the expression of major fibrillar collagens including collagen 1α1, 1α2 and 3α1 compared to WT TAC mice. Echocardiography revealed a broad improvement in myocardial systolic and diastolic function in TAC-operated scleraxis conditional null mice compared to WT TAC animals.

Conclusions: Our results demonstrate the important role of scleraxis in governing multiple processes that contribute to fibrosis, including matrix expression and remodeling. Abrogating the function of scleraxis may be beneficial for the treatment of cardiac fibrosis.

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