Protective role of normothermic, hyperthermic and estrogen preconditioning and pretreatment on tumour necrosis factor-alpha-induced damage

Although reperfusion therapy is the gold standard for the survival of ischemic tissue and the prevention of further ischemic damage, it can also cause unavoidable damage to myocardial tissue by initiating a series of events involving both intracellular and extracellular mechanisms (1). Murry et al (2) were the pioneers in the field of preconditioning (PC). They introduced the idea that stimulating the heart before sustained ischemia can protect the cardiomyocytes from ischemia reperfusion (I/R) damage. Later, the same findings were reported by another study (3). Several methods of PC were shown to be effective in protecting the heart (4–10). However, the role of some pharmacological PC methods and the synergy in different PC methods are not completely understood. Furthermore, the role of some elements, such as tumour necrosis factor-alpha (TNF-α) in I/R damage or PC protection, is not clear. Several studies have shown TNF-α to be detrimental to the heart, contributing to myocardial dysfunction and cardiomyocyte death in myocardial I/R injury (11). I/R injury is reported to be associated with increased TNF-α expression (11). TNF-α was also reported to be a contributing factor in the deterioration observed in other heart diseases (12). It has been shown to be an apoptotic agent in many cell types (including those in the heart) (13). Other studies suggested that it may be a trigger for ischemic PC (IPC) protection (14,15). Therefore, the effects of TNF-α must be carefully examined to discriminate between its detrimental and protective roles. The effects of 17-beta estradiol (E2) on the heart are far from being understood. Although it was shown to be protective against I/R damage (16), it was contradictorily proven to be detrimental in other studies (17). Recently, some studies (18,19) showed that pretreatment of the heart with E2 could protect against subsequent I/R damage. It was also shown that pretreatment with E2 can offer protection similar to that of IPC (20). Although the evidence is limited, the use of E2 in PC has shown significant protection against I/R injury (6). In 2006, Xu et al (10) reported that E2 modulates TNF-α expression and the expression of its receptors. Controversial results were also reported by another study (21). In the present study, we investigated the detrimental effects of TNF-α on the heart and the salvage action of normothermic IPC (NIPC), hyperthermic IPC (HIPC) and E2 PC. We also evaluated the protective effect of combining two methods – HIPC and E2 PC or E2 pretreatment – against TNF-α-associated damage.