Changes in Hsp90 expression determine the effects of cyclosporine A on the NO pathway in rat myocardium.
Cyclosporine A (CsA) is associated with the development of cardiovascular toxicity in transplant patients but can exert myocardial protection against ischemia/reperfusion damages. We examined in a rat model of chronic CsA administration whether subtle variations in the NO pathway could account for these opposite effects. CsA treatment rapidly led to an increase in myocardial Hsp90 expression promoting the recruitment of Akt and calcineurin, thereby promoting eNOS activation through Ser1177 phosphorylation and Thr495 dephosphorylation, respectively. This was associated with an increase in myocardial VEGF expression and led to anti-apoptotic effects in isolated cardiac myocytes. Upon longer CsA exposure, cardiac toxicity developed, as documented by the infiltration of connective tissue and the increase in iNOS expression. These later effects were associated with a dramatic decrease in the abundance and scaffold function of Hsp90, thereby unraveling the key role of Hsp90 in governing CsA effects.
Rezzani
Rita
R
Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
Rodella
Luigi
L
Dessy
Chantal
C
Daneau
Géraldine
G
Bianchi
Rossella
R
Feron
Olivier
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D016228:Endothelial Growth Factors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000737:chemistry / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D018841:HSP90 Heat-Shock Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D016572:Cyclosporine; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases