This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bunda, S. Articles by Hinek, A. Search for Related Content PubMed PubMed Citation Articles by Bunda, S. Articles by Hinek, A.

(American Journal of Pathology. 2007;171:809-819.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070101

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

Severa Bunda^*, Peter Liu, Yanting Wang^*, Kela Liu^* and Aleksander Hinek^*

From the Cardiovascular Research Program,^* The Hospital for Sick Children, Department of Laboratory Medicine and Pathobiology, and the Heart and Stroke/Richard Lewar Centre for Excellence, University of Toronto; the Toronto General Hospital/University Health Network, Toronto, Ontario; and the Institute of Circulatory and Respiratory Health, Canadian Institutes of Health Research, Toronto, Ontario, Canada

Aldosterone is known to regulate electrolyte homeostasis, but it may also contribute to other processes, including the maladaptive remodeling of postinfarct hearts. Because aldosterone has been implicated in the stimulation of collagen production in the heart, we investigated whether it would also affect elastin deposition in cultures of human cardiac fibroblasts. We first demonstrated that treatment with 1 to 50 nmol/L aldosterone leads to a significant increase in collagen type I mRNA levels and in subsequent collagen fiber deposition. Pretreatment of cells with the mineralocorticoid receptor antagonist spironolactone, but not with the glucocorticoid receptor antagonist RU 486, inhibited collagen synthesis in aldosterone-treated cultures. Most importantly, we demonstrated that aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition in a dose-dependent manner. Strikingly, neither spironolactone nor RU 486 eliminated aldosterone-induced increases in elastin production. We further discovered that the proelastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor and that the insulin-like growth factor-I receptor kinase inhibitor AG1024 or an anti-insulin-like growth factor-I receptor-neutralizing antibody inhibits both insulin-like growth factor-I and aldosterone-induced elastogenesis. Thus, we have demonstrated for the first time that aldosterone, which stimulates collagen production through the mineralocorticoid receptor-dependent pathway, also increases elastogenesis via a parallel mineralocorticoid receptor-independent pathway involving I insulin-like growth factor-I receptor signaling.