Angiotensin II directly increases transforming growth factor beta 1 and osteopontin and indirectly affects collagen mRNA expression in the human heart

Objectives: Angiotensin II (Ang II) induces fibroblast proliferation and co llagen synthesis in the myocardium, but its precise mechanisms of action in human hearts are still unknown. Therefore, we investigated whether Ang II directly affects the collagen mRNA content in the human myocardium and in i solated human cardiac fibroblasts or whether the growth factors TGF beta-1 and osteopontin are involved in this process. Methods and results I: In a f irst set of experiments, the direct effect of Ang II on collagen I, TGF bet a-1 and osteopontin mRNA content in fresh samples of human atrial myocardiu m was determined by the use of a short stimulation period. After 4 h, Ang I I-stimulated atrial samples gave a significantly higher expression of both TGF beta-1 (183+/-21% of control, p<0.05) and osteopontin mRNA (275+/-58%, p<0.02) than the controls. In contrast, the expression of collagen I mRNA w as unchanged (95+/-8%). Stimulation with TGF beta-1 led to an increase in c ollagen I and III mRNA (127+10%, p<0.05; 140+/-15%, p<0.02). Methods and re sults II: In a second protocol, to assess the effects of longer stimulation periods, we determined the effects of Ang II and its potential mediator TG F beta-1 on collagen I, III and fibronectin mRNA expression and on prolifer ation of cultured human cardiac fibroblasts. Ang II caused a dose-dependent stimulation of proliferation but did not affect collagen I, III or fibrone ctin mRNA content after 24 h. In contrast, TGF beta-1 stimulation significa ntly increased collagen I and III mRNA expression (124+/-5% and 128+/-5%, p <0.002). Conclusions: In the human heart, Ang II does not directly increase collagen or fibronectin mRNA, but it does increase TGF beta-1 and osteopon tin mRNA expression. Since TGF beta-1 induces collagen I and III mRNA in at rial samples and in isolated cardiac fibroblasts, it may represent a necess ary mediator of the Ang II effects in the human heart. (C) 2000 Elsevier Sc ience B.V. All rights reserved.