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 improvemen t in the prognosis of solid organ transplantation. However, drug-induced hy pertension and nephrotoxicity, associated with the development of atheroscl erosis and coronary heart disease, still worsen the long-term outcome of Cs A-treated patients. Whether the CsA-induced myocardial changes are associat ed with the induction of connective tissue growth factor (CTGF), a recently found polypeptide implicated in extracellular matrix synthesis, is not kno wn. Methods, Spontaneously hypertensive rats (8-9 weeks old) were treated with CsA (5 mg.kg(-1).d(-1) subcutaneously) for 6 weeks. The influence of angiot ensin-converting enzyme inhibition (enalapril 30 mg.kg(-1).d(-1) orally) an d angiotensin-1 receptor blockade (valsartan 3 and 30 mg.kg(-1).d(-1) orall y) on CsA toxicity was also investigated. Myocardial morphology was examine d, and vascular lesions were scored. Localization and the quantitative expr ession 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 m yocardial 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 myocar dial lesions. Blockade of the renin-angiotensin system prevented vascular d amage and the CsA-induced CTGF, collagen I, and collagen III mRNA overexpre ssions in the heart. Conclusions. CsA increases CTGF, collagen I, and collagen III mRNA expressi ons in the heart. The induction of CTGF gene is mediated, at least in part, by angiotensin II.