Role of p38 mitogen-activated protein kinase pathway in estrogen-mediated cardioprotection following trauma-hemorrhage

Abstract

IH. Role of p38 mitogenactivated protein kinase pathway in estrogen-mediated cardioprotection following trauma-hemorrhage. Am J Physiol Heart Circ Physiol 292: H2982-H2987, 2007. First published February 9, 2007 doi:10.1152/ajpheart.01303.2006.-p38 mitogen-activated protein kinase (MAPK) activates a number of heat shock proteins (HSPs), including HSP27 and ␣ B-crystallin, in response to stress. Activation of HSP27 or ␣ B-crystallin is known to protect organs/cells by increasing the stability of actin microfilaments. Although our previous studies showed that 17␤-estradiol (E 2) improves cardiovascular function after trauma-hemorrhage, whether the salutary effects of E 2 under those conditions are mediated via p38 MAPK remains unknown. Male rats (275-325 g body wt) were subjected to soft tissue trauma and hemorrhage (35-40 mmHg mean blood pressure for ϳ90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were injected intravenously with vehicle, E 2 (1 mg/kg body wt), E2 ϩ the p38 MAPK inhibitor SB-203580 (2 mg/kg body wt), or SB-203580 alone, and various parameters were measured 2 h thereafter. Cardiac functions that were depressed after trauma-hemorrhage were returned to normal levels by E 2 administration, and phosphorylation of cardiac p38 MAPK, HSP27, and ␣ B-crystallin was increased. The E2-mediated improvement of cardiac function and increase in p38 MAPK, HSP27, and ␣ B-crystallin phosphorylation were abolished with coadministration of SB-203580. These results suggest that the salutary effect of E2 on cardiac function after trauma-hemorrhage is in part mediated via upregulation of p38 MAPK and subsequent phosphorylation of HSP27 and ␣B-crystallin.

Activation and Clinical Significance of p38 MAPK Signaling Pathway in Patients With Severe Trauma

“…However, it was reported that after traumatic bleeding, up-regulation of p38 MAPK signaling pathway can activate heat shock protein such as HSP27 and a B-crystallin by phosphorylation, and induces the cell protective effect of the body [23]. In addition, activation of p38 MAPK is associated with wound healing because p38 MAPK influences the motions of many types of cells that take an important part in the healing process, such as immune cells, fibroblasts, epithelial cells.…”

Mechanism of salutary effects of estrogen on cardiac function following trauma-hemorrhage: Akt-dependent HO-1 up-regulation*

“…All experiments were performed in adherence with National Institutes of Health (Bethesda, MD) Guidelines for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of the University of Alabama at Birmingham. A nonheparinized model of trauma-hemorrhage was used as described previously (1,31). Briefly, rats were anesthetized by isoflurane inhalation before the induction of soft tissue trauma via 5-cm midline laparotomy.…”

“…In this regard, we have found that cardiac function is depressed in male animals and ovariectomized females but not in proestrus females, a state with the highest plasma levels of 17␤-estradiol (E2) following trauma-hemorrhage (31)(32)(33)(34). Additional findings have indicated that precastration of males resulted in normalization of cardiac function following trauma-hemorrhage (1).…”

Estrogen, NFκB, and the Heat Shock Response

“…These effects were not seen during other phases of the estrus cycle, when estrogen levels are lower (26,27). E2 supplementation in ovariectomized females and male rats attenuated the depressed cardiovascular function associated with trauma-hemorrhage through activation of p38 MAPK and PI3-K/AKT (28,29).…”

“…In addition, E2 stimulates the phosphorylation of HSP 27 and αβ-crystallin via p38 MAP kinase, essential for the protective properties of these proteins (28). Further evidence of E2 increasing expression of HSPs are the observations that intact females have higher levels of HSP 72 than males, both basally and following ischemia/reperfusion, in cardiac and renal tissue (95,98).…”