The Critical Role of Scleraxis in Pressure Overload‐Induced Cardiac Fibrosis

Cardiac fibrosis is an independent risk factor for patient morbidity and mortality that is caused by other forms of cardiovascular dysfunction, including myocardial infarction, pressure overload and diabetes, yet lacks any current treatment options. A required step in the pathogenesis of fibrosis is the activation of fibroblasts to myofibroblasts, which secrete high levels of matrix proteins including collagen, resulting in elevated myocardial wall stiffness, loss of compliance and arrhythmias. We previously demonstrated that the transcription factor scleraxis is both sufficient and necessary to drive the phenotype conversion of fibroblasts to myofibroblasts via direct transactivation of key pro‐fibrotic proteins such as collagen 1α2, α‐smooth muscle actin and fibronectin. We hypothesized that genetic deletion of scleraxis would be sufficient to prevent cardiac fibrosis. We used a tamoxifen‐inducible fibroblast‐specific Cre recombinase mouse line (Tcf21‐iCre) crossed to a floxed scleraxis line to permit timed deletion in adult animals. Eight week old mice were gavaged with tamoxifen to induce scleraxis gene deletion, followed by pressure overload (thoracic aortic constriction, TAC) or sham surgery; scleraxis‐intact animals received corn oil carrier. Animals were sacrificed at 4 or 8 weeks post‐surgery and analyzed for cardiac fibrosis and function. Deletion of scleraxis significantly attenuated TAC‐induced up‐regulation of major matrix proteins including collagen 1α1, 1α2, 3α1 and ED‐A fibronectin compared to scleraxis‐intact TAC mice. Masson's trichrome staining revealed that scleraxis deletion drastically reduced fibrotic areas within the myocardium compared to scleraxis‐intact TAC mice. Cardiac structural and functional analysis by echocardiography demonstrated a broad improvement in myocardial systolic and diastolic function in TAC‐operated scleraxis conditional null mice compared to scleraxis‐intact TAC animals, despite the persistency of cardiac hypertrophy in null mice. Ejection fraction and fractional shortening were significantly improved by scleraxis deletion, as was left ventricular internal diameter at both systole and diastole, while heart size normalized to body weight or tibia length was unaffected. While E/A ratio – an indicator of diastolic function – was not altered by TAC at the time points employed in this study, both early and late ventricular filling velocities were decreased in scleraxis‐intact TAC mice, and normalized in scleraxis null mice. Our results show that scleraxis is required for the up‐regulation of extracellular matrix proteins and fibrosis following pressure overload. Intriguingly, scleraxis gene deletion improved cardiac structure and function despite a lack of effect on overall hypertrophy, demonstrating that ameliorating fibrosis alone has salutary benefits. Targeting scleraxis should thus be explored as a potential means of treating cardiac fibrosis. Support or Funding Information RSN was the recipient of a PhD Graduate Studentship from Research Manitoba; MPC was supported by an Open Operating Grant from the Canadian Institutes of Health Research (MOP136862). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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