Expression of follistatin-related genes is altered in heart failure

Follistatins play roles in diverse biological processes including cell proliferation, wound healing, inflammation and skeletal muscle growth yet their role in the heart is currently unknown. We have investigated the myocardial expression profile and cellular distribution of follistatin (FST) and the follistatin-like genes FSTL1 and FSTL3 in the normal and failing heart. Expression was further analysed in the novel setting of recovery from heart failure in myocardium obtained from patients who received combined mechanical (left ventricular assist device; LVAD) and pharmacologic therapy. Real-time PCR revealed that FSTL1 and FSTL3 expression was elevated in heart failure but returned to normal following recovery. FSTL3 expression levels correlated with molecular markers of disease severity and FSTL1 with the endothelial cell marker CD31, suggesting a potential link with vascularization. FSTL1 levels prior to treatment correlated with cardiac function following recovery suggesting initial levels may influence long term outcome. Immunohistochemistry revealed that FST was primarily localized to fibroblasts and vascular endothelium within the heart, whereas FSTL1 was localized to myocytes, endothelium and smooth muscle cells, and FSLT3 to myocytes and endothelium. Microarray analysis revealed that FST and FSTL1 were associated with extracellular matrix-related and calcium binding proteins, whereas FSTL3 was associated mainly with cell signalling and transcription. These data show for the first time that elevated myocardial expression of follistatin-like genes is a feature of heart failure and may be linked to both disease severity and mechanisms underlying recovery, revealing new insight into the pathogenesis of heart failure and offering novel therapeutic targets.