Abstract:
17
β
-estradiol (E2) treatment activates a set of protective response that have been found to protect
cells from injury and more importantly to significantly abate the injuries associated with trauma-
hemorrhage
in vivo
. Rapid NF
κ
B activation has been found to be an important signaling step in
E2 mediated protection in cell culture,
in vivo
ischemia and trauma-hemorrhage. In the current
study, we investigated the signaling cascades linking E2 signaling with NF
κ
B activation and the
protective response, and compared them with the effects of two selective estrogen receptor
modulators (SERMs), raloxifene and tamoxifen. Two candidate pathways, mitogen activated
protein kinases (MAPK), and phosphatidylinositol-3-kinase (PI3-K) were studied. Selective
inhibitors were used to identify each pathway's contribution to NF
κ
B activation. Treatment of
HCAECs with E2 activated PI3-K/Akt, p38, and JNK, all of which activated ERK 1/2 followed by
NF
κ
B activation. The combined activation of Akt, p38 and JNK was essential to activate NF
κ
B.
The two SERMs activated PI3-K and p38, which then phosphorylated ERK 1/2 and activated
NF
κ
B independent of the JNK pathway. NFkB activation by these compounds protected cells
from hypoxia/reoxygenation injury. However, E2, unlike either SERM, led to modest increases in
apoptosis through the JNK pathway. SERM treatment led to increased expression of the protective
proteins, Mn-superoxide dismutase and endothelial nitric oxide synthase, that was not seen with
E2. These results provide new insight into the pathways activating NFkB by E2 and SERMS and
demonstrate that SERMs may have greater protective benefits than E2 in adult endothelial cells
and potentially
in vivo
, as well