Cardiomyopathy in Murine Models of Systemic Sclerosis

Abstract

Objective. Cardiomyopathy has emerged as a leading cause of death in patients with systemic sclerosis (SSc). However, the pathogenesis of SSc-related cardiomyopathy is poorly understood, and new therapies as well as platforms for testing are needed. The aim of this study was to characterize the histopathologic features of cardiomyopathy in patients with SSc and in common mouse models of SSc.Methods. The histopathologic features of myocardial tissue specimens obtained at autopsy from 5 subjects with SSc and 5 control subjects matched for sex, age, and cardiovascular risk factors were evaluated and compared with those of myocardial tissue specimens obtained from 3 common mouse models of SSc with systemic manifestations: Fra-2-transgenic mice, mice with sclerodermatous chronic graft-versus-host disease (GVHD), and TSK-1 mice.Results. Myocardial tissue from autopsy subjects with SSc and no clinically manifest cardiac involvement showed endothelial cell apoptosis with reduced capillary density, perivascular inflammation, myofibroblast differentiation, and accumulation of collagen. Only selected features of SSc-related cardiomyopathy were observed in the mice with chronic GVHD and TSK-1 mice. However, the myocardial tissue of Fra-2-transgenic mice mimicked all features of SSc-related cardiomyopathy and also demonstrated comparable vascular, inflammatory, and fibrotic manifestations. Of note, the expression of Fra-2 was also increased in the myocardium of autopsy subjects with SSc.Conclusion. We demonstrate that all typical manifestations of SSc-related cardiomyopathy are mimicked in Fra-2-transgenic mice. Moreover, overexpression of Fra-2 in the myocardium of autopsy subjects with SSc may suggest similar underlying pathogenic mechanisms. Thus, Fra-2-transgenic mice might be a suitable preclinical model with which to study the mechanisms of and therapeutic approaches to myocardial involvement in SSc.

Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis

“…Myocardial changes in patients with SSc are mimicked in Fra2 transgenic mice 21. Treatment with nintedanib at 60 mg/kg/qd reduced the extent of fibrosis, ameliorated perivascular inflammation and decreased apoptosis of endothelial cells (see online supplementary figure S2A–F).…”

Systemic sclerosis-like histopathological features in the myocardium of uPAR-deficient mice

“…On the basis of the main histopathological features commonly reported in the myocardium of patients with SSc,2 7 10 13 we systematically assessed left and right ventricular myocardial specimens from our uPAR-deficient mice, focusing on the possible presence of (i) cardiomyocyte damage, (ii) collagen accumulation and α-smooth muscle actin (α-SMA)-positive myofibroblast differentiation, (iii) perivascular inflammation, and (iv) endothelial cell apoptosis with reduced capillary density. Following our previous report on uPAR-deficient mice,11 two different time points were included in the analyses, namely 12 and 24 weeks of age.…”

“…In this context, Venalis et al 10 have recently investigated myocardial involvement in different murine models of SSc, including Fra-2 transgenic mice, mice with sclerodermatous chronic graft-versus-host disease (GVHD) and TSK-1 mice. Mice with chronic GVHD and TSK-1 mice presented only certain features of SSc-related cardiomyopathy, while Fra-2 transgenic mice, a model with coexisting vascular alterations and multiorgan fibrosis, mimicked all major histopathological features of SSc-associated myocardial disease 10…”

“…However, owing to the paucity of clinical samples and the lack of suitable animal models, the pathogenetic mechanisms underlying SSc-related cardiomyopathy remain mostly unknown. Interestingly, recent experimental evidence indicates that histopathological features of SSc-related cardiomyopathy may be mimicked by murine models of SSc, especially fos-related antigen 2 (Fra-2) transgenic mice 10. In this context, urokinase-type plasminogen activator receptor (uPAR)-deficient mice are a recently described animal model displaying important histopathological hallmarks of SSc, such as dermal fibrosis, dermal endothelial cell apoptosis with reduced capillary density, and progressive pulmonary fibrosis with non-specific interstitial pneumonia-like features 11 12…”

Animal Models of Systemic Sclerosis

“…In addition, Fra-2 transgenic mice develop severe vascular remodeling of pulmonary arteries and nonspecific interstitial pneumonia-like interstitial lung disease resembling human systemic sclerosis-associated pulmonary hypertension [95]. Finally, recent studies have indicated that Fra-2 transgenic mice show all the traits of SSc-related cardiomyopathy [96]. In contrast to bleomycin-or HOCl-mice, Fra-2 transgenic mice do not display any activation of PDGFR-(Platelet Growth Factor Receptor -) in the skin, [97,98].…”