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Review Article


Kher, Ajay*,‡; Wang, Meijing*,‡; Tsai, Ben M*; Pitcher, Jeffrey M*; Greenbaum, Evan S; Nagy, Ryan D*; Patel, Ketan M*; Wairiuko, G Mathenge*; Markel, Troy A*; Meldrum, Daniel R*,†,‡

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Shock 23(1):p 1-10, January 2005. | DOI: 10.1097/01.shk.0000148055.12387.15
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The inflammatory response to injury is a double-edged sword that plays an important part in the damage produced by the injury, as well as in the process of repair. In the heart, it has been shown that the inflammatory response is produced not only by resident macrophages, but also by cardiomyocytes (1, 2). The cytokines produced during an inflammatory response cause depression of cardiac function (3-5), hence methods that block the inflammatory response may be protective (6-8). Sex differences have been noted in these responses and the potential reasons for the differences have been the subject of extensive research (9, 10). This review will examine evidence for gender differences in the outcome to acute injury, explain the myocardial inflammatory response to acute injury, elucidate the various mechanisms by which gender affects the myocardial response to acute injury.


Gender differences have been noted in outcome to acute injuries like myocardial infarction, burns, trauma, and sepsis. Hospital-based clinical studies have shown that women have a higher mortality rate after myocardial infarction compared with men (11-13). In general, the women in many of these studies were older, had higher risk factors (diabetes, hypertension, and congestive heart failure), more complications, and lower likelihood of receiving treatment (14). Importantly, more men died of myocardial infarction before reaching the hospital, and the 28-day mortality for men and women was the same (15-17). This actually suggests that women are relatively protected in the immediate aftermath of a myocardial infarction, but are similar to men at the end of 1 month.

Sepsis and trauma are two other inflammatory conditions associated with sex-dependent outcomes. Some studies suggest that there is no sex difference in mortality after trauma (18-20), while others suggest that there is sex difference in blunt trauma but not in penetrating trauma (21). Studies that have found sex differences are inconsistent. Some studies showed a benefit only in women >50 years old (21), whereas others showed a benefit only in women <50 years old (22, 23). However, women have a lower incidence of pneumonia, sepsis, and multiorgan failure after trauma (19, 23-25). In sepsis, some studies have found a higher mortality rate in women >80 years old (26), whereas others have found lower mortality rates for women (27). In a study by Schroder and colleagues (28) involving patients with sepsis, women demonstrated lower mortality, higher interleukin 10 (IL-10), and lower tumor necrosis factor-α (TNF-α) levels. Fewer female patients in intensive care units developed sepsis, although once sepsis developed, the mortality rate was the same (29). Clinical studies on sex differences in mortality after burns present inconsistent evidence. Some showed that women (30) or only women age 30 to 59 years (31) had higher mortality, whereas others showed that women had a lower incidence of multiorgan dysfunction and sepsis after burns (32).

In contrast to the clinical studies, animal studies have consistently found that females do better. Protective effects of acute administration of estrogen in an in vivo left anterior descending (LAD) coronary artery ischemia/reperfusion (I/R) model have been shown in different animals (33-36). Chronic administration of estrogen provides protection from I/R injury in isolated hearts undergoing global ischemia and in hearts undergoing in vivo LAD obstruction (37, 38). Estrogen also protected against reperfusion-induced arrhythmias after LAD I/R injury (35, 38, 39). Ovariectomized females have worse cardiac functional recovery after global I/R, in an isolated heart, than do sham ovariectomized females or ovariectomized females with estradiol replacement (40, 41). After burn injury, females have lower cytokine production and better cardiac function (42). Trauma-hemorrhage leads to depressed immune function and this depression is more severe in males (43-45). The immune depression is in part caused by testosterone (46, 47) because castration (44) and receptor blockade (48-51) attenuated this depression. Estrogen also prevented the immune depression caused by trauma-hemorrhage (52, 53).

Animal studies have consistently shown that females are protected against acute injury, whereas clinical studies appear inconsistent. A possible reason is that in animal studies, the female population is well controlled and only proestrous females are used, whereas clinical studies have a heterogeneous population. Furthermore, the underlying condition of humans is less uniform. Indeed, the few animal studies that used diestrous females showed that diestrous females had functional recovery equivalent to males, but lower than proestrous females (42, 54). This has been borne out by a few clinical studies that showed that cardiac function fluctuates with the hormonal changes of menstrual cycle (55-57). Thus, it is important to know the hormonal status of females, and future clinical studies that take this into account may produce more consistent results. The remainder of this review will focus on gender differences in the myocardial inflammatory response to acute injury.


Acute injuries lead to the production of an inflammatory cascade. The inflammatory cascade is triggered through many pathways, but it may converge into a few key regulatory proteins. Perhaps important among these are p38 mitogen-activated protein kinase (MAPK) and nuclear factor κB (NFκB). I/R, sepsis, trauma, and burn injury lead to oxidative stress (1, 58), which activates p38 MAPK (59-61) and NFκB (Fig. 1A) (62, 63). p38 MAPK is regulated by upstream kinases referred to as MAPK kinase (MAPKK), which themselves are regulated by MAPKK kinases (MAPKKK). This sequence of phosphorylation causes amplification of the signal. p38 MAPK is crucial in the cascade leading to TNF gene induction, and its inhibition is protective (Fig. 1B) (64-68). p38 MAPK is also involved in the production of IL-1, IL-4, IL-6, and IL-8 (69-72). Wang and colleagues (66) showed that the increase in TNF, IL-1, and IL-6 production, after endotoxin infusion in an isolated heart, could be inhibited by a p38 MAPK inhibitor. TNF sequestration alone led to a decrease in IL-1 and IL-6. This suggests that TNF is upstream to IL-1 and IL-6 and that the effect of p38 MAPK on other cytokines might be mediated through TNF.

Fig. 1.:
The effects of estrogen on myocardial response to acute injury. Plain lines indicate activation or increase, and dash and dot lines indicate inhibition or decrease. (A) Sepsis, I/R, trauma, and burns lead to oxidant stress. The oxidant stress activates p38 MAPK, NFκB, and causes leukocyte accumulation. Estrogen increases antioxidants and inhibits the oxidant stress. (B) p38 MAPK is activated by lipopolysaccharide (LPS) through protein tyrosine kinase, TNF, IL-1, and oxidative stress. p38 MAPK activates NFκB through inhibitory κ B kinase (IKK), and NFκB increases TNF production. (C) TNF produces leukocyte accumulation and apoptosis and increases nitric oxide (NO). NO decreases leukocyte accumulation and decreases intracellular calcium concentration. (D) Sympathetic stimulation through β adrenergic receptors (β AR) causes upregulation of expression of sodium-calcium exchanger (NCX) and increases the affinity of sarcoplasmic reticulum (SR) calcium ATPase (SRCA) for calcium. SRCA and NCX then act during injury to increase the intracellular calcium concentration. (E) Estrogen inhibits p38 MAPK activation and hence decreases the production of TNF. Estrogen increases the nuclear localization of Akt and Akt inhibits apoptosis. Estrogen increases NO production and activates ATP-sensitive potassium channels (KATP) and through them, decreases the intracellular concentration of calcium. Estrogen decreases the expression of β AR.

NFκB is involved in the regulation of many processes, including apoptosis, cell growth, stress responses, innate and acquired immunity, and sepsis. NFκB is bound to inhibitory κ B (IκB) in the cytoplasm, and this prevents its nuclear localization and DNA binding. Phosphorylation of IκB by inhibitory κ B kinase (IKK) results in dissociation of IκB from NFκB, allowing NFκB to translocate to the nucleus. MAPK, protein kinase C, and phosphatidylinositol 3 kinase (PI3K)/Akt converge on IKK for NFκB activation (73, 74). p38 MAPK plays an important role in activation of NFκB and expression of NFκB-dependent genes (Fig. 1B) (67, 73, 75, 76). NFκB activation leads to production of TNF-α and IL-1 (Fig. 1B) (77-79).

MAPK and NFκB activation also occur through other mechanisms. TNF and IL-1 activate p38 MAPK and NFκB (Fig. 1B). IL-1 leads to the formation of a complex between IL-1 receptor-associated kinase (IRAK) and myeloid differentiation factor 88 (MyD88) (80, 81). IRAK is released and binds to TNF-receptor associated factor (TRAF). TRAF activates a MAPKKK, which activates p38 MAPK and NFκB (82). TNF also activates them through TRAF. TNF and IL-1 activate p38 MAPK and NFκB, and they increase the production of TNF and IL-1, thus forming a feed-forward mechanism and amplifying the inflammatory response. LPS, through its interaction with CD14, provokes rapid activation of protein tyrosine kinase, which activates a pathway involving Ras/Raf-1/MEK/MAPK/NFκB (Fig. 1B) (1). Recently, LPS has also been shown to use the MyD88/IRAK pathway (74, 83). These pathways have been delineated, but their roles in myocardial inflammatory response to sepsis is not known and should be the subject of further research.

TNF causes decreased myocardial contractile efficiency and reduced ejection fraction, hypotension, decreased systemic vascular resistance, and biventricular dilation. These effects are produced through calcium dyshomeostasis, direct cytotoxicity, oxidant stress, disruption of excitation-contraction coupling, myocyte apoptosis, and induction of other cardiac depressant cytokines such as IL-1 and IL-6 (1). TNF, through sphingosine, disrupts L-type channel-induced calcium (LCC) release and thereby depresses calcium transients (84-86). NO appears to mediate TNF-induced desensitization of myofilaments to intracellular calcium (Fig. 1C) (87, 88). Anti-TNF measures have been protective, however, a study using TNF receptor knockout mice showed increased infarcts in the knockout mice after LAD occlusion (89). This suggests that TNF leads to activation of protective and damaging responses, and that a decrease in the excessive TNF production after acute injury may be protective but a complete absence is harmful. This might be why clinical studies of anti-TNF measures have not shown the benefit expected (90).

TNF, IL-1, and IL-6 lead to increased expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) (91-93). Neutrophil adhesion occurs, leading to a respiratory burst that produces reactive oxygen species (94). The importance of neutrophils in cardiac injury is made clear by the cardioprotection obtained with neutrophil depletion (95-97). The reactive oxygen species produced during acute injury can also cause leukocyte chemotaxis (98) and adhesion (99), possibly through complement activation (100), upregulating P selectin expression (101), by inducing ICAM-1 expression (102) or by increasing the ability of ICAM-1 to bind neutrophils (103). Protective effects of antioxidant enzymes were shown in left circumflex coronary artery I/R by infusing antioxidant enzymes (104) and in isolated hearts of transgenic mice overexpressing antioxidant enzymes (105, 106). Disappointingly, clinical studies using them have found no significant benefit (107, 108).


Sex differences in cytokine production after acute injury have been shown in many studies. In clinical studies, Schroder and colleagues (28) showed that women had lower TNF and higher IL-10 levels in sepsis, and Oberholzer and associates (19) showed that male trauma patients had higher IL-6 levels. In animal studies, females had lower cardiomyocyte secretion and serum concentrations of TNF, IL-1, IL-6, and IL-10 after burn injury (42). Deshpande and colleagues (109) showed that estradiol attenuated the LPS-induced production of IL-1, IL-6, and TNF by macrophages and also decreased NFκB-binding activity. Estradiol also attenuated the increase in IL-6 after trauma-hemorrhage (110). As stated earlier, trauma-hemorrhage leads to depressed immune function, and this depression is more severe in males (43-45). The immune depression is in part caused by testosterone (46, 47) because castration (44) and receptor blockade (48-51) attenuated this depression. Estrogen also prevented the immune depression caused by trauma-hemorrhage (52, 53). Although gender difference in the cytokine production after acute injury has been noted, the mechanisms by which these differences are mediated are not known.

p38 MAPK

As p38 MAPK is an important regulatory protein in the inflammatory cascade, recent evidence showing sex differences in p38 MAPK point toward a possible role for it in mediating sex differences in response to acute injury. Sex differences in p38 MAPK activation have been shown after trauma-hemorrhage and I/R. Wang and colleagues (111) found that males had higher levels of phosphorylated p38 MAPK (the activated form of p38 MAPK) in isolated hearts after global I/R. They also showed that ovariectomized females had phosphorylated p38 MAPK equivalent to males and that treatment of males and ovariectomized females with estradiol prevented the increase in phosphorylated p38 MAPK caused by I/R. This suggests that the decreased cytokine production and cardioprotection caused by estrogen might be mediated through p38 MAPK (Fig. 1E).

Chaudry’s group (112) presented interesting findings on p38 MAPK activation after trauma-hemorrhage. They showed that gender did not alter the expression of the nonphosphorylated p38 MAPK in macrophages, but did alter the expression of phosphorylated p38 MAPK. Macrophages from female shams had increased phosphorylated p38 MAPK compared with males. Trauma-hemorrhage increased phosporylated p38 MAPK in males, but decreased it in females. They also showed that castration attenuated the increase in phosphorylated p38 MAPK caused by trauma-hemorrhage and that supplementation with 5α dihydrotestosterone restored the ability of trauma-hemorrhage to activate p38 MAPK. This suggests that testosterone leads to p38 MAPK activation after trauma-hemorrhage (Fig. 2E). The significance of the gender difference in p38 MAPK in shams is not known, and it will be interesting to see if it is valid in humans and other animals, and whether it leads to differences in cytokine production. Both studies show higher p38 MAPK activity after acute injury in males, suggesting that acute injuries lead to activation of similar pathways and that p38 MAPK is involved (111, 112). Previous studies indicate that after trauma-hemorrhage, there is a decreased capability of macrophages to release cytokines and that this is more severe in males. This raises the question as to whether increased p38 MAPK activation in males is the cause for the immune depression, and, if it is, why does it lead to immune depression instead of activation. A hypothesis proposed by Chaudry’s group (112) that integrates all of the evidence is that the increased p38 MAPK activation leads to such an increase in the inflammatory cytokine response that it leads to an exhaustion of the capacity of the cells to respond to any further stimulus.

Fig. 2.:
The effects of testosterone on myocardial response to acute injury. Plain lines indicate activation or increase, and dash and dot lines indicate inhibition or decrease. (A) Sepsis, I/R, trauma, and burns lead to oxidant stress. The oxidant stress activates p38 MAPK, NFκB, and causes leukocyte accumulation. (B) p38 MAPK is activated by LPS through protein tyrosine kinase, TNF, IL-1, and oxidative stress. p38 MAPK activates NFκB through IKK, and NFκB increases TNF production. (C) TNF produces leukocyte accumulation and apoptosis, and increases NO. NO decreases leukocyte accumulation and decreases intracellular calcium concentration. (D) Sympathetic stimulation through β AR causes upregulation of expression of NCX and increases the affinity of SRCA for calcium. SRCA and NCX then act during injury to increase the intracellular calcium concentration. (E) Testosterone upregulates the expression of β AR, NCX, and LCC, and through these, increases the intracellular calcium concentration. Testosterone promotes apoptosis, although the mechanism is not clearly defined.

These studies have shown that estradiol and testosterone modify p38 MAPK and that this may be responsible for gender differences in response to acute injury, although further studies are needed to clarify the issue.


As oxidant stress is one of the stimuli for inflammatory cytokine production, any gender difference in antioxidants could lead to differences in the inflammatory response to acute injury. The sudden increase in production of hydroxyl radicals that occurs during reperfusion was reduced by estrogen in a canine model of LAD I/R (113). Using a similar I/R model, it was found that estrogen decreased lipid peroxidation, and in an in vitro study, estrogen decreased superoxide anion production from coronary artery segments undergoing hypoxia/reoxygenation (38). A possible mechanism for the antioxidant effect of estrogen is increased reduced glutathione (GSH) in the myocardium. This was supported by using a GSH synthesis antagonist, which reduced GSH and partially reversed the beneficial effects of estrogen on left ventricular diastolic pressure, systolic shortening, and lipid peroxidation after LAD I/R (114). As there was only a partial reversal by using a GSH synthesis antagonist, other mechanisms must also play a role in the protective effects of estrogen.

Another possible antioxidant mechanism is increased levels of superoxide dismutase in females. Barp and colleagues (115) showed decreased lipid peroxidation and increased superoxide dismutase in female hearts compared with males. Ovariectomized females had a significant decrease in superoxide dismutase and an increase in lipid peroxidation. However, this study did not induce acute injury and hence the role of these changes in the protective effects seen in females after acute injury is unknown.

Oxygen radicals have also been shown to upregulate expression of adhesion molecules. Squadrito and colleagues (116) showed that estrogen decreased serum and macrophage TNF levels and decreased ICAM-1 expression in the myocardium after left main coronary artery I/R. This led to decreased leukocyte accumulation and smaller infarcts in the estradiol-treated group. Other studies have also shown that estrogen decreases neutrophil accumulation after LAD I/R (33, 34). The mechanism by which estrogen decreases the leukocyte accumulation is not well defined, although there is evidence supporting a role for antioxidant mechanisms, NO, and decreased TNF production (Fig. 1, A and C).


Many physiological and pharmacological actions have been attributed to NO, and several of these are cardioprotective. The protective effects appear dependent on endothelial NO synthase (eNOS) (117) and inducible NOS (iNOS) (118). Estrogen increases NO production through increased expression of iNOS and eNOS in cardiomyocytes (35, 119-122). NO provides protection by reducing the expression of adhesion molecules, especially P selectin, and decreasing neutrophil accumulation (Fig. 1C) (123, 124). Increased infarct size occurred when an NOS inhibitor was used (125). NO also modulates calcium channels and affects myocardial contractility.

Cardiac contraction is triggered by calcium release through LCC and SR. During relaxation, NCX and SRCA act to remove intracellular free calcium. Increase in intracellular calcium occurs with myocardial ischemia, and inhibition of this is protective (126, 127). NO decreases free intracellular calcium by inhibiting LCC (128, 129) and inhibiting the calcium release from SR (130-132). The inhibition of calcium release from SR may be mediated by inactivation of ryanodine receptor calcium release channel by NO (131). NO may also modulate calcium by activating or potentiating the effects of KATP channels (133, 134). Thus, estrogen leads to increased production of NO and through it decreases neutrophil accumulation and free intracellular calcium and provides cardioprotection (Fig. 1C).

β AR and SRCA

The sympathetic stimulation that occurs after acute injury acts through β AR to increase cAMP and cAMP-dependent protein kinase A. This kinase phosphorylates many effector proteins, one of them being phopholamban (PLB). PLB is an SR protein that when phosphorylated, dissociates from SRCA and increases the affinity of SRCA for calcium (135). This leads to increased SR calcium, increased SR calcium release, and increased myocardial contractility (136-138). Golden and coworkers (139) have shown that protein kinase A also increases expression of NCX. Thus, β adrenergic stimulation not only increases calcium release from SR, but also increases NCX expression (Fig. 1D). These pathways lead to increased intracellular calcium and increased myocardial contractility, but after acute injury, these same pathways lead to increased damage.

Estrogen and progesterone depletion causes upregulation of β AR in the heart and this was reversed by supplementation of estrogen or progesterone (140). Estrogen deficiency led to increased density of β AR in the heart, although the affinity remained the same. Isoproterenol (selective β AR agonist) increases infarct size in isolated hearts undergoing I/R, but estrogen protects against the injury produced by it (141). The increased damage caused by β AR is probably due to increased accumulation of intracellular calcium after injury.

Using PLB-knockout mice, Cross and colleagues (142) found that the knockout mice had greater baseline myocardial contractility but worse myocardial recovery after I/R. This study confirmed the fact that increased calcium through SRCA leads to increased baseline myocardial contractility but it also leads to increased damage after acute injury. They also found that female knockout mice recovered better from I/R compared with male knockout mice. The use of L-NAME (an NOS inhibitor) blocked the protective effects in females, and giving S-nitroso-N-acetylpenicillamine (an NO donor) to males provided protection equivalent to female knockouts. In another study, when isolated hearts were treated with isoproterenol or high Ca2+, increased I/R injury was found in males (143). Females were protected against this injury but lost the protection when treated with L-NAME. The probable mechanism by which NO provides this protection is by inhibiting the ryanodine receptor calcium release channel and thereby inhibiting calcium release from cardiac SR.

Castration causes a reduction in the myocardial expression of β AR, LCC, and NCX, and supplementation with androgens reversed these effects (Fig. 2E) (144). This led to reduced contractility in cardiomyocytes from castrated males. Thus, androgens lead to increased contractility through these mechanisms. The impact of these changes on myocardial damage after acute injury has not been studied, but it can be postulated that the increased calcium influx produced by them would lead to increased myocardial injury.


Horton and colleagues (42) found that the cardiomyocyte secretion of inflammatory cytokines after burns by diestrous rats was similar to males, but that the sodium/calcium (Na+/Ca2+) accumulation was significantly less and diestrous rats had better cardiac function. This suggested that differences in Na+/Ca2+ accumulation are instrumental in mediating sex differences in cardiac function after burns. NCX is present on the sarcolemmal membrane and countertransports three Na+ ions for one Ca2+ ion. NCX can function in either direction depending on the transmembrane gradients of the ions and the membrane potential. A role for this protein in myocardial injury was suspected because manipulations of intracellular sodium led to corresponding changes in intracellular calcium and that affected the myocardial injury produced (145, 146). NCX normally works in the calcium removal mode, but in ischemia, there is an increase in intracellular Na+ and change in the membrane potential, which leads to reversing of the NCX (147). Isolated hearts of transgenic male mice overexpressing NCX had greater I/R injury than wild-type mice (148). Female transgenic mice were protected from the increased I/R injury compared with male transgenics, and this protection was lost partially when female transgenic mice were ovariectomized. The mechanism of the protective effect in these transgenic females is unknown, as male and female transgenic hearts did not have a difference in the overexpression of NCX. The possible mechanisms are that females are better able to withstand the higher intracellular calcium produced by NCX overexpression or that even with similar NCX overexpression, females have lower intracellular calcium due to lower intracellular sodium. Evidence in support of the latter has been provided by Sugishita and colleagues (149). They studied myocytes isolated from NCX-overexpressing mice and they found lower intracellular calcium after metabolic inhibition in females. They also found lower intracellular sodium in females, suggesting that the decreased calcium in females might be because of this. Due to the stoichiometry of NCX (exchanges three sodium ions for one calcium ion) even small differences in intracellular sodium would lead to larger differences in calcium. This suggests that females may be protected due to lower intracellular sodium after acute injury, although the reason for the lower intracellular sodium in females remains unanswered.

KATP channels

KATP channels have been shown to be present in cardiac mitochondria and to mediate protection against ischemic injury. These channels are activated by many stimuli, including adenosine (150), NO (134), and free radicals, and these then activate protein kinase C, which links to mitochondrial KATP channels (151, 152). Mitochondrial calcium overload plays an important part in I/R injury (153, 154). The opening of mitochondrial KATP channels results in potassium influx, which decreases the driving force for calcium uptake (Fig. 1E) (155). The use of KATP channel agonists has shown the decreased mitochondrial calcium concentration caused by the opening of KATP channels (156). Estrogen has been shown to decrease infarct size in canine LAD I/R through mitochondrial KATP channels (157) and to decrease reperfusion-induced arrhythmias through sarcolemmal KATP channels (158). The mechanism by which estrogen activates these channels is unknown. The evidence that estrogen increases NO production and that NO can activate these channels indicates that this might be a possible mediator. Estrogen has been used in coronary angioplasty patients and has been shown to reduce myocardial ischemia caused by balloon inflation, possibly through KATP channels (159).


Apoptosis is a genetically controlled process by which cells undergo non-necrotic cellular death. Testosterone has been shown to promote apoptosis in vascular endothelial cells (160) and renal tubular cells (161), whereas anabolic-androgenic steroids do so in cardiomyocytes (162). Verzola and colleagues (161) showed a dose-dependent effect of testosterone on apoptosis in renal tubular cells. They also showed that testosterone upregulated Fas, Fas ligand, and Fas-associated death domain. The use of caspase-3 inhibitor, caspase-8 inhibitor, or caspase-9 inhibitor reduced the apoptosis produced by testosterone. Testosterone was shown to decrease Bcl-2 expression (160). These studies indicate the possible role of testosterone in promoting apoptosis, although further research is needed to delineate the mechanisms.

Estrogen has been shown to decrease apoptosis of cardiac myocytes induced by staurosporine, and this was associated with decreased caspase 3 activity and decreased NFκB (163). Wang and colleagues (111) showed that females had lower active caspase 3 and caspase 8, but higher Bcl-2 after global I/R in isolated hearts. They also showed that ovariectomized females had increased active caspase-3, whereas estradiol administration to males and ovariectomized females reduced the level of active caspase-3. Camper-Kirby and colleagues (164) found that females have higher nuclear localization of phospho-Akt in myocardium. Akt kinase activity in female nuclei was higher and the nuclei had higher phospho-forkhead levels (which is a downstream target of Akt). Administration of estradiol increased nuclear localization of phopho-Akt (Fig. 1E). Akt has previously been shown to inhibit apoptosis in cardiomyocytes in I/R (165, 166). It has also been shown to mediate the antiapoptotic effects of insulin growth factor-1 (167). The possible mechanisms of the antiapoptotic effects of Akt are phosphorylation of BcL-xL/BcL-2 associated death promoter, (168) phosphorylation of caspase 9 (169), and phosphorylation of FKHRL1, which leads to the blocking of Fas ligand expression (170). This suggests that Akt might be a mediator for the antiapoptotic effect of estrogen after acute injury.

TNF is also known to produce apoptosis. TNF induces apoptosis by binding to TNF type 1 receptor or Fas (1, 83). Both are associated with death domains, TNF receptor-associated death domain and Fas-associated death domain. These death domains interact with receptor-interaction protein and activate endonucleases. The endonucleases destroy the nuclear DNA, leading to apoptosis. As stated earlier, estrogen decreases TNF production after acute injury and hence may decrease the apoptosis produced by TNF.

In summary, sex differences exist in the response of the heart to acute injury. The role of estrogen has been actively studied and it decreases inflammatory cytokine production and provides protection against acute injury. Many protective effects of estrogen have been shown, which include decreased p38 MAPK activation, an antioxidant effect, increased NO production, modulation of calcium influx and release, activation of KATP channels, and decreased apoptosis. The effects of testosterone on myocardial inflammatory response are being explored. The available evidence indicates that testosterone increases p38 MAPK activation, upregulates expression of β AR and calcium channels, and induces apoptosis. These differences provide opportunities for therapeutic manipulations, but further research is needed to clarify the importance of the different mechanisms and the interactions between them.


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Cytokines; trauma-hemorrhage; ischemia/reperfusion; sepsis; burns; heart; gender

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