Cyclosporine A- induces cardiac remodeling through TGF-β/Smad3/miR-29 signaling pathway and gene expression alteration of miR-30b-5p/ CaMKIIδ isoforms pathway: alleviated effect of moderate exercises

Abstract

Purpose Cyclosporine A (CsA)-induced cardiac interstitial fibrosis and cardiac hypertrophy is a highly known phenomenon, whereas the basic mechanisms of CsA cardiotoxicity are not clear yet. The present study evaluated the role of the TGF-β/Smad3/miR-29b signaling pathway and CaMKIIδ isoforms gene expression in cardiac remodeling under sole CsA exposure or in combination with moderate exercises. Methods A total of 24 male Wistar rats were divided into three groups as follows: control, cyclosporine (30mg/kg BW), and cyclosporine-exercise groups. Results After 42 days of treatment, the findings revealed a significant decline in miR-29 and miR-30b-5p gene expression, increases in gene expression of Smad3, calcium/calmodulin-dependent protein kinaseIIδ (CaMKIIδ) isoforms, Matrix Metalloproteins (MMPs), protein expression of TGF-β, heart tissue protein carbonyl and oxidized LDL (Ox-LDL), as well as plasma LDL and cholesterol levels in CsA treated group in comparison to the controls. The CsA group, in comparison to the controls, presented histological heart changes like fibrosis, necrosis, hemorrhage, infiltrated leukocyte, and left ventricular weight/ heart weight. Moderate exercise and CsA, relatively improved gene expression changes and histological alternation in comparison to the CsA group. Conclusion These findings suggested that TGF-β-Smad3-miR-29 and CaMKIIδ isoforms may somehow have a main contribution to the progression of heart fibrosis and hypertrophy due to CsA exposure, which provides new insight into the pathogenesis and treatment of CsA induced side effects on heart tissue.