Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression

Abstract

-Although studies indicate that 17␤-estradiol administration after trauma-hemorrhage (T-H) improves cardiac and hepatic functions, the underlying mechanisms remain unclear. Because the induction of heat shock proteins (HSPs) can protect cardiac and hepatic functions, we hypothesized that these proteins contribute to the salutary effects of estradiol after T-H. To test this hypothesis, male Sprague-Dawley rats (ϳ300 g) underwent laparotomy and hemorrhagic shock (35-40 mmHg for ϳ90 min) followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17␤-estradiol (1 mg/kg body wt) was administered at the end of the resuscitation. Five hours after T-H and resuscitation there was a significant decrease in cardiac output, positive and negative maximal rate of left ventricular pressure. Liver function as determined by bile production and indocyanine green clearance was also compromised after T-H and resuscitation. This was accompanied by an increase in plasma alanine aminotransferase (ALT) levels and liver perfusate lactic dehydrogenase levels. Furthermore, circulating levels of TNF-␣, IL-6, and IL-10 were also increased. In addition to decreased cardiac and hepatic function, there was an increase in cardiac HSP32 expression and a reduction in HSP60 expression after T-H. In the liver, HSP32 and HSP70 were increased after T-H. There was no change in heart HSP70 and liver HSP60 after T-H and resuscitation. Estradiol administration at the end of T-H and resuscitation increased heart/liver HSPs expression, ameliorated the impairment of heart/liver functions, and significantly prevented the increase in plasma levels of ALT, TNF-␣, and IL-6. The ability of estradiol to induce HSPs expression in the heart and the liver suggests that HSPs, in part, mediate the salutary effects of 17␤-estradiol on organ functions after T-H. heme oxygenase-1; organ dysfunction; tumor necrosis factor-␣; estrogen; injury THE DELETERIOUS EFFECTS OF hemorrhagic shock and septic shock on organ functions are well established (12,34,41). Nonetheless, studies have also shown that upregulation of heat shock protein (HSP) under the same conditions has protective effects (18,19,35,38). HSPs, sometimes termed molecular chaperones, are highly conserved intracellular proteins that play an important role in the folding of the newly synthesized proteins and prevent the aggregation of denatured proteins (9). In addition, a particular HSP, HSP32, also known as heme oxygenase-1, appears to act as a potent vasodilator and antioxidant-producing agent in many organs against insults, such as ischemia and oxidative stress (22). HSP upregulation was first observed with hyperthermia, but other stresses, such as ischemia, free radicals, or proinflammatory cytokines can also induce their expression (24). Furthermore, HSP induction appears to play a critical role in the protection against the pathophysiological effects of low-flow states, since its induction results in protection, whereas their inhibition leads to exacerbation of the injury (...

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

“…Our previous studies showed that cardiac output was significantly decreased in the trauma-hemorrhage rats and was restored to normal after E 2 administration following trauma-hemorrhage (11,41). Furthermore, ϩdP/dt max and ϪdP/dt max can reflect the value of cardiac output in sham and trauma-hemorrhage rats.…”

“…HSPs are induced by exposure to a number of different stresses, including heat and ischemia, and they help minimize the damaging effect of such stress on the heart (20,26). Our previous studies showed that administration of 17␤-estradiol (E 2 ) after trauma-hemorrhage restores cardiac function through upregulation of HSP expression (41,45). Furthermore, studies have demonstrated that HSP27 and ␣ B -crystallin are downstream of p38 MAPK (6,8,10).…”

Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury

“…␣-Glutathione S-transferase (␣-GST) is a highly sensitive and specific biomarker of hepatic injury (4,35). At 2 h after resuscitation, plasma samples were obtained.…”

The role of estrogen receptor subtypes in ameliorating hepatic injury following trauma-hemorrhage

“…The mechanisms responsible for the gender dimorphic response include differences in proinflammatory cytokine, reactive oxygen species, and vasoregulatory action [16,17]. Our previous studies have shown that administration of female sex steroid hormone, 17b-estradiol (E2) [18,19], or androgen receptor antagonist, flutamide [20], protects hepatic function following trauma-hemorrhage. Furthermore, recent studies have suggested that the salutary effects of E2 on organ function after trauma-hemorrhage are mediated in part via upregulation of Hsps [18].…”

“…Our previous studies have shown that administration of female sex steroid hormone, 17b-estradiol (E2) [18,19], or androgen receptor antagonist, flutamide [20], protects hepatic function following trauma-hemorrhage. Furthermore, recent studies have suggested that the salutary effects of E2 on organ function after trauma-hemorrhage are mediated in part via upregulation of Hsps [18]. There are two estrogen receptors (ERs), ER-a and ER-b, which are differentially expressed in different tissues [21].…”