Cardiac
fibrosis is a biological process that increases with age and contributes to myocardial dysfunction.
Humanin (HN) is an endogenous mitochondria-derived
peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac
fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo
intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased
collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by
picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5'-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-β1,
fibroblast growth factor-2, and
matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial
fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/
glycogen synthase kinase -3β pathway in aged mice. Exogenous HNG treatment attenuated myocardial
fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived
peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac
fibrosis is a biological process that increases with age and contributes to myocardial dysfunction.
Humanin is an endogenous mitochondria-derived
peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous
humanin treatment attenuated myocardial
fibrosis and apoptosis in aging mice. We also detected upregulated Akt/
glycogen synthase kinase-3β pathway in
humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of
humanin analog in aging mice.