This study aimed to investigate the anti-fibrotic effects of
ghrelin in
isoproterenol (ISO)-induced myocardial
fibrosis and the underlying mechanism. Sprague-Dawley rats were randomized to control, ISO, and ISO +
ghrelin groups. ISO (2 mg/kg per day, subcutaneous) or vehicle was administered once daily for 7 days, then
ghrelin (100 microg/kg per day, subcutaneous) was administered once daily for the next 3 weeks.
Ghrelin treatment greatly improved the cardiac function of ISO-treated rats.
Ghrelin also decreased plasma
brain natriuretic peptide level and ratios of heart weight to
body weight and left ventricular weight to
body weight.
Ghrelin significantly reduced myocardial
collagen area and
hydroxyproline content, accompanied by decreased
mRNA levels of
collagen type I and III. Furthermore,
ghrelin increased plasma level of
growth differentiation factor 15 (GDF15) and GDF15
mRNA and
protein levels in heart tissues, which were significantly decreased with ISO alone. The phosphorylation of Akt at Ser473 and
GSK-3beta at Ser9 was decreased with ISO, and
ghrelin significantly reversed the downregulation of p-Akt and p-GSK-3beta. Mediated by GDF15,
ghrelin could attenuate ISO-induced myocardial
fibrosis via Akt-GSK-3beta signaling.