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Abstract
<p class="first" id="d668667e302">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;
<i>n</i> = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group,
<i>n</i> = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group,
<i>n</i> = 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-β
<sub>1</sub>, 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.
</p><p id="d668667e316">
<b>NEW & NOTEWORTHY</b> 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.
</p>