Our previous study demonstrated that
zinc prevents cardiac
reperfusion injury by targeting the
mitochondrial permeability transition pore (mPTP) via Akt and
glycogen synthetase kinase 3beta (GSK-3beta). We aimed to address the mechanism by which
zinc activates Akt. Treatment of H9c2 cells with ZnCl(2) (10 microM) in the presence of the
zinc ionophore pyrithione (4 microM) for 20 min enhanced Akt phosphorylation (Ser(473)), indicating that
zinc can rapidly activate Akt.
Zinc did not alter either
phosphatase and
tensin homolog deleted on chromosome 10 (PTEN) phosphorylation and total
PTEN protein levels or PTEN oxidation, implying that PTEN may not play a role in the action of
zinc. However,
zinc-induced Akt phosphorylation was blocked by both the nonselective
receptor tyrosine kinase (RTK) inhibitor
genistein and the selective
insulin-like growth factor-1 RTK (IGF-1RTK) inhibitor
AG1024, indicating that
zinc activates Akt via IGF-1RTK.
Zinc-induced phosphorylation of
protein tyrosine and Ser/Thr was also abolished by
AG1024. In addition,
zinc markedly enhanced phosphorylation of
IGF-1 receptor (IGF-1R), which was again reversed by
genistein and
AG1024. A confocal imaging study revealed that
AG1024 abolished the preventive effect of
zinc on
oxidant-induced
mPTP opening, confirming that IGF-1RTK plays a role in
zinc-induced cardioprotection. Furthermore,
zinc decreased the activity of
protein phosphatase 2A (PP2A), a major
protein Ser/Thr
phosphatase, implying that
protein Ser/Thr
phosphatases may also play a role in the action of
zinc on Akt activity. Taken together, these findings demonstrate that exogenous
zinc activates Akt via IGF-1RTK and prevents the
mPTP opening in cardiac cells. Inactivation of Ser/Thr
protein phosphatases may also contribute to
zinc-induced Akt activation.