Cyclosporine A induces cardiac remodeling through TGF-β/Smad3/miR-29 signaling pathway and alters gene expression of miR-30b-5p/CaMKIIδ isoforms pathways: alleviating effects of moderate exercise.

Abstract

Cyclosporine A (CsA)-induced cardiac interstitial fibrosis and cardiac hypertrophy are highly known phenomena; however, the basic mechanisms of CsA cardiotoxicity are unclear. The present study evaluated the role of the Transforming growth factor-beta (TGF-β)/Smad3/miR-29b signaling pathway and CaMKIIδ isoforms gene expression in cardiac remodeling under CsA exposure alone or combined with moderate exercise. A total of 24 male Wistar rats were divided into control, cyclosporine (30mg/kg BW), and cyclosporine-exercise groups. After 42 days of treatment, the findings revealed a significant decline in miR-29 and miR-30b-5p gene expression and an increase in gene expression of Smad3, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) isoforms, Matrix Metalloproteinases (MMPs), protein expression of TGF-β, heart tissue protein carbonyl and oxidized LDL (Ox-LDL), and plasma LDL and cholesterol levels in the CsA-treated group compared to the control group. The CsA group presented greater histological heart changes such as fibrosis, necrosis, hemorrhage, infiltrated leukocyte, and left ventricular weight/heart weight than the control group. Moreover, combined moderate exercise and CsA relatively improved gene expression changes and histological alternations compared to the CsA group. TGF-β-Smad3-miR-29 and CaMKIIδ isoforms may mainly contribute to the progression of heart fibrosis and hypertrophy due to CsA exposure, providing new insight into the pathogenesis and treatment of CsA-induced side effects on the heart tissue.