Abstract: | ObjectivesThis study was designed to evaluate the interaction between aging and obesity
on cardiac contractile and intracellular Ca2+
properties.MethodsCardiomyocytes from young (4-mo) and aging (12- and 18-mo) male lean and the
leptin deficient ob/ob obese mice were treated with leptin
(0.5, 1.0 and 50 nM) for 4 hrs in vitro. High fat diet
(45% calorie from fat) and the leptin receptor mutant
db/db obesity models at young and older age were used
for comparison. Cardiomyocyte contractile and intracellular
Ca2+ properties were evaluated including peak
shortening (PS), maximal velocity of shortening/relengthening (±
dL/dt), time-to-PS (TPS), time-to-90% relengthening
(TR90), intracellular Ca2+ levels and
decay. O2
− levels were measured by
dihydroethidium fluorescence.ResultsOur results revealed reduced survival in ob/ob mice. Aging
and obesity reduced PS, ± dL/dt, intracellular
Ca2+ rise, prolonged TR90 and
intracellular Ca2+ decay, enhanced
O2
− production and
p
47phox expression
without an additive effect of the two, with the exception of intracellular
Ca2+ rise. Western blot analysis exhibited reduced
Ob-R expression and STAT-3 phosphorylation in both young and aging
ob/ob mice, which was restored by leptin. Aging and
obesity reduced phosphorylation of Akt, eNOS and p38 while promoting pJNK
and pIκB. Low levels of leptin reconciled contractile, intracellular
Ca2+ and cell signaling defects as well as
O2
− production and
p
47phox upregulation in
young but not aging ob/ob mice. High level of leptin (50
nM) compromised contractile and intracellular Ca2+
response as well as O2
− production and
stress signaling in all groups. High fat diet-induced and
db/db obesity displayed somewhat comparable
aging-induced mechanical but not leptin response.ConclusionsTaken together, our data suggest that aging and obesity compromise cardiac
contractile function possibly via phosphorylation of Akt, eNOS and stress
signaling-associated O2
− release. |