Elevated fibrotic response of the right ventricle is due to innate fibroblast characteristics

Abstract

The right ventricle (RV) of the heart normally encounters low pressure and high volume, but under increased afterload from elevated vascular resistance or outflow tract obstruction, undergoes adaptive hypertrophy followed by maladaptive remodeling. This is similar to what is found in left ventricle pathology (LV) except that RV dysfunction features exaggerated cardiac fibrosis compared to that found in the LV, which greatly worsens clinical outcomes. We sought to investigate the cellular environment of the rat RV in an effort to discover novel treatment strategies for RV dysfunction in failure found in patients with cor pulmonale. Sprague‐Dawley rats treated in hypoxia (10% O2) developed RV dysfunction as noted via echocardiography (decreased tricuspid annular plane systolic excursion, P<0.05 via t‐test) and increased RV weight relative to the LV and septum (P<0.05 via t‐test) compared to control rats (room air). Trichrome staining revealed that hypoxia‐treated rats had perfuse interstitial fibrosis in the RV, but not the LV. Expression of fibrotic mediators was increased in the RV of both control and hypoxia‐treated rats, including fibronectin‐1, periostin, and connective tissue growth factor (CTGF), but not collagen 1, as revealed by qPCR. These differences in gene expression indicate not only does hypoxia cause increased fibrosis in the RV, but also that the RV has innately increased fibrotic factors even under control conditions compared to the LV. This was supported by immunofluorescent imaging of vimentin, an intermediate filament expressed in fibroblasts, which displayed higher expression in the RV of control rats compared to the LV, with strongest expression in the RV of hypoxia‐treated rats. To investigate the role of fibroblasts in RV hypertrophy, we performed enzymatic tissue digests to obtain cultured fibroblasts. Fibroblasts isolated from the RV of both hypoxia‐ and normoxia‐treated rats proliferated at a faster rate and treatment with TGF‐β caused a greater response in the fibroblasts from the RV compared to the LV as measured by expression of periostin and CTGF. Thus, our results demonstrate that the RV, as compared to the LV, is primed for a fibrotic response. This may explain the exaggerated fibrotic phenotype found in both human RV disease and animal models of RV hypertrophy.