IGF-IIR plays important roles as a key regulator in myocardial pathological
hypertrophy and apoptosis, which subsequently lead to
heart failure. Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb used to treat
cardiovascular diseases.
Tanshinone IIA is an active compound in Danshen and is structurally similar to 17[Formula: see text]-
estradiol (E[Formula: see text]. However, whether
tanshinone IIA improves cardiomyocyte survival in pathological
hypertrophy through
estrogen receptor (ER) regulation remains unclear. This study investigates the role of ER signaling in mediating the protective effects of
tanshinone IIA on IGF-IIR-induced myocardial
hypertrophy. Leu27IGF-II (
IGF-II analog) was shown in this study to specifically activate IGF-IIR expression and
ICI 182,780 (ICI), an ER antagonist used to investigate
tanshinone IIA estrogenic activity. We demonstrated that
tanshinone IIA significantly enhanced Akt phosphorylation through ER activation to inhibit Leu27IGF-II-induced
calcineurin expression and subsequent
NFATc3 nuclear translocation to suppress myocardial
hypertrophy.
Tanshinone IIA reduced the cell size and suppressed
ANP and BNP, inhibiting antihypertrophic effects induced by Leu27IGF-II. The cardioprotective properties of
tanshinone IIA that inhibit Leu27IGF-II-induced cell
hypertrophy and promote cell survival were reversed by ICI. Furthermore, ICI significantly reduced phospho-Akt,
Ly294002 (PI3K inhibitor), and PI3K
siRNA significantly reduced the
tanshinone IIA-induced protective effect. The above results suggest that
tanshinone IIA inhibited cardiomyocyte
hypertrophy, which was mediated through ER, by activating the PI3K/Akt pathway and inhibiting Leu27IGF-II-induced
calcineurin and
NFATC3.
Tanshinone IIA exerted strong estrogenic activity and therefore represented a novel selective ER modulator that inhibits IGF-IIR signaling to block
cardiac hypertrophy.