Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

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Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

Authors

Tamiato, A.; Tombor, L. S.; Fischer, A.; Muhly-Reinholz, M.; Vanicek, L. R.; Togru, B. N.; Neitz, J.; Glaser, S. F.; Merten, M.; Rodriguez Morales, D.; Kwon, J.; Klatt, S.; Schuhmacher, B.; Guenther, S.; Abplanalp, W. T.; John, D.; Fleming, I.; Wettschureck, N.; Dimmeler, S.; Luxan, G.

Abstract

Background: Ageing is one of the main risk factors of cardiovascular disease. Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. In the heart, the consequences of ageing on cardiac pericytes are unknown. Methods: In this study, we have combined single nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 loss of function and finally have perfomed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 loss of function in pericytes on the neighbouring fibroblasts. Results: We showed that ageing reduces the pericyte area and coverage. Single nucleus RNA sequencing analysis further revealed that the expression of the Regulator of G protein signalling 5 (Rgs5) is reduced in old cardiac pericytes. In vivo and in vitro studies showed that the deletion of RGS5 induces morphological changes and a pro-fibrotic gene expression signature characterized by the expression of different extracellular matrix components and growth factors like TGFB2 and PDGFB in pericytes. Indeed, the culture of fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation characterized by the increased expression of smooth muscle actin in a TFG{beta}2 dependent mechanism. Conclusions: Our results identify RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.

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