Cyclosporine induces myocardial connective tissue growth factor in spontaneously hypertensive rats on high-sodium diet.
BACKGROUND
The introduction of cyclosporine (CsA) has led to an improvement in the prognosis of solid organ transplantation. However, drug-induced hypertension and nephrotoxicity, associated with the development of atherosclerosis and coronary heart disease, still worsen the long-term outcome of CsA-treated patients. Whether the CsA-induced myocardial changes are associated with the induction of connective tissue growth factor (CTGF), a recently found polypeptide implicated in extracellular matrix synthesis, is not known.


METHODS
Spontaneously hypertensive rats (8-9 weeks old) were treated with CsA (5 mg x kg(-1) x d(-1) subcutaneously) for 6 weeks. The influence of angiotensin-converting enzyme inhibition (enalapril 30 mg x kg(-1) x d(-1) orally) and angiotensin-1 receptor blockade (valsartan 3 and 30 mg x kg(-1) x d(-1) orally) on CsA toxicity was also investigated. Myocardial morphology was examined, and vascular lesions were scored. Localization and the quantitative expression of CTGF, as well as collagen I and collagen III, mRNA were evaluated by in situ hybridization and Northern blot.


RESULTS
CsA-induced hypertension and nephrotoxicity were associated with myocardial infarcts and vasculopathy of the coronary arteries. CsA increased myocardial CTGF, collagen I, and collagen III mRNA expressions by 91%, 198%, and 151%, respectively. CTGF mRNA expression colocalized with the myocardial lesions. Blockade of the renin-angiotensin system prevented vascular damage and the CsA-induced CTGF, collagen I, and collagen III mRNA overexpressions in the heart.


CONCLUSIONS
CsA increases CTGF, collagen I, and collagen III mRNA expressions in the heart. The induction of CTGF gene is mediated, at least in part, by angiotensin II.
Finckenberg
P
P
Biomedicum Helsinki, Institute of Biomedicine/Pharmacology, University of Helsinki, Finland.
Lassila
M
M
Inkinen
K
K
Pere
A K
AK
Krogerus
L
L
Lindgren
L
L
Mervaala
E
E
Vapaatalo
H
H
Nurminen
M L
ML
Ahonen
J
J
D000818:Animals; D003094:Collagen / Q000235:genetics; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006133:Growth Substances / Q000235:genetics*; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D017874:Immediate-Early Proteins / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics*; D011921:Rats, Inbred WKY; D012982:Sodium, Dietary / Q000008:administration & dosage* / Q000494:pharmacology
C526316:CCN2 protein, rat; D006133:Growth Substances; D017874:Immediate-Early Proteins; D007166:Immunosuppressive Agents; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D012982:Sodium, Dietary; D055513:Connective Tissue Growth Factor; D016572:Cyclosporine; D003094:Collagen