Adverse effects of cyclosporine A on HSP25, alpha B-crystallin and myofibrillar cytoskeleton in rat heart.
Cyclosporine (CsA) is a universally used immunosuppressive drug which induces adverse side effects in several organs, but its impact on the heart is still controversial. Small heat shock proteins (sHSPs), such as HSP25 and alpha B-crystallin, are cytoprotective stress proteins exceptionally represented in the heart. They act as myofibrillar chaperones that help actin and desmin to maintain their optimum configuration and stability, thereby antagonizing oxidative damage. The present study examined: (1) the cardiac distribution and abundance of HSP25 and alpha B-crystallin in rats receiving CsA at a therapeutic dosage (15 mg/kg/day) for 42 days and 63 days; (2) the presence of myofibrillar proteins, such as actin, alpha-actinin and desmin following the CsA treatments; (3) the subcellular effects of prolonged CsA exposure on the cardiomyocytes by histopathology and transmission electron microscopy. After 63 days CsA intake, sHSPs translocated from a regular sarcomeric pattern to peripheral sarcolemma and intercalated discs, together with actin and desmin. In contrast, the sarcomeric alpha-actinin pattern did not change in all experimental groups. The abundance of actin and HSP25 was unchanged in every time point of treatment while after 63 days CsA, alpha B-crystallin and desmin levels significantly decreased. Furthermore CsA induced fibrosis, irregular sarcomeric alignment and damaged desmosomes. These findings indicate that following prolonged CsA exposure, the cardiac muscle network was affected. In particular, the translocation of sHSPs to intercalated discs merits special consideration as a direct compensatory mechanism to limit CsA cardiotoxicity.
Stacchiotti
Alessandra
A
Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, V.le Europa 11, I-2513 Brescia, Italy.
Bonomini
Francesca
F
Lavazza
Antonio
A
Rodella
Luigi Fabrizio
LF
Rezzani
Rita
R
D000185:Actinin / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D003893:Desmin / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced; D055551:HSP27 Heat-Shock Proteins / Q000187:drug effects* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008297:Male; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D038203:alpha-Crystallin B Chain / Q000187:drug effects* / Q000378:metabolism
D000199:Actins; D003893:Desmin; D055551:HSP27 Heat-Shock Proteins; C486114:Hspb1 protein, rat; D007166:Immunosuppressive Agents; D038203:alpha-Crystallin B Chain; D000185:Actinin; D016572:Cyclosporine