Date Published: February 01, 2019
Publisher: JKL International LLC
Author(s): Dong Liu, Liqun Xu, Xiaoyan Zhang, Changhong Shi, Shubin Qiao, Zhiqiang Ma, Jiansong Yuan.
Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy. Special focus is placed on the roles of mTOR during ischemic and IR injury. We then clarify the association between mTOR and conditioning phenomena. Following this background, we expand our discussion to potential future directions of research in this area. Collectively, information reviewed herein will serve as a comprehensive reference for the actions of mTOR in IR injury and may be significant for the design of future research and increase the potential of mTOR as a therapeutic target.
The disease state of ischemia results from a hypoperfusion-induced insufficiency of oxidative metabolism due to inadequate blood circulation and the incidence of ischemia increase with age [2, 84]. Accumulating evidences indicate that mTOR is involved in ischemic injury and mTORC1 is inhibited during acute ischemia which preserves the energy status through the reduction of cellular energy expenditure and activation of autophagy and promotes survival [17, 72, 85]. Activation of mTOR during ischemia may lead to decreased autophagy and increased ischemic injury . Rapamycin reduces myocardial infarction in the diabetic mice heart via inhibiting mTOR thus activating the Janus kinase 2 (JAK2) /signal transducer and activator of transcription 3 (STAT3) signaling pathway  (Fig. 2B). It recently demonstrated that mTORC1 was inhibited during ischemia through the inhibition of Ras homolog enriched in brain (Rheb) which directly binds and activates mTORC1 [22, 88, 89]. Mice with partial cardiac Rheb deletion display better cardiac function after experimental myocardial infarction and a reduction of infarct size as compared with control mice, indicating Rheb inhibition is beneficial and corroborating the protective effect of mTORC1 inhibition during acute ischemia . Furthermore, ischemic injury of skeletal muscles is a common pathophysiology during peripheral vascular injury and surgeries [85, 91], which usually induces significant necrosis and apoptosis in the skeletal muscle cells. Endothelial mTORC1 deletion protects against hindlimb ischemic injury in diabetic mice possibly via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation .
Reperfusion is mandatory to salvage acutely ischemic tissues from infarction. However, the process of restoring blood ?ow to the ischemic organs or tissues can also contribute to irreversible injury [106, 107], which appears to reflect an oxidant burden established upon reoxygenation of ischemic tissues or organs . IR induces cytosolic and mitochondrial calcium overload, oxidative stress, rapid restoration in intracellular pH, which on a background of relative adenosine triphosphate (ATP) depletion, culminates in the opening of the mitochondrial permeability transition pore (mPTP) and free radical-induced irreversible mitochondrial damage . Advancing age is a strong risk factor for IR injury [109, 110]. The age-related physiological or pathological changes in the cellular components have been shown to increase the vulnerability of IR injury [109-111]. Aging heart is more sensitive to IR injury, and cardiac mitochondrial function has a significant decline in aging, including mitochondrial Ca2+ handling decline and mitochondrial ROS generation/oxidative damage [112, 113]. It was demonstrated that mTORC1 is rapidly activated and exerts protective effects during the reperfusion phase . Consistent with the idea that mTORC1 exerts a protective effect during reperfusion damage, cardiac-specific mTOR overexpression reduces chronic cardiac remodeling after IR in vivo  (Fig. 3). Below we will discuss the different signaling pathways and the protective effects of mTOR regulation in IR injury (Fig. 2B).
Although extensive research suggests that mTOR activation exerts protective effects during IR injury, some studies have shown that mTOR may play a deleterious role in reperfusion injury. Simvastatin reduces IR injury through the inhibition of mTOR and activation of mitophagy . Testicular IR injury is usually induced by torsion/detorsion, and inhibition mTOR reduces the apoptosis on IR damage in rat testis [15, 146, 147]. Additionally, attenuating Akt/mTOR/ p70S6K pathway reduces kidney inflammation and apoptosis after hepatic IR . Suppression of mTORC1 through activation of AMPK results in enhancement of protective autophagy and protects heart and kidney against IR injury [5, 12, 148]. Interestingly, upregulation of SIRT1 inhibits mTOR activity via AMPK activation thus protecting liver grafts from the IR injury associated with orthotopic liver transplantation . It has been reported that mTOR inhibition by rapamycin protects the heart by selective activation of ERK and inhibition of p38 MAPK during reperfusion injury . Moreover, mTORC1 inhibition via restraining the p38 MAPK activation induces protective autophagy cerebral during IR injury . The negative effects of mTOR that is contrary to previous results may be explained by the level of activation of autophagy during reperfusion injury. Autophagy was also induced by ischemia and further enhanced by reperfusion. We can be hypothesized that if the cellular stress is manageable and the activation of autophagy is protective during reperfusion, it would be deleterious to activate mTOR; if the damage is beyond repair and the activation of autophagy is excessive, activation of mTOR would be beneficial.
An increasing number of efforts have attempted to search for proper agents for the treatment of IR injury [16, 125, 126, 148]. There is currently no stronger protection than that by the conditioning phenomena although the effectiveness of conditioning decreases with age [151-153]. Ischemic conditioning means applying brief episodes of nonlethal IR to confer protection against a sustained episode of lethal IR injury, which was originally discovered in 1986 by Murry et al. and termed ‘ischemic preconditioning’ . The protective stimulus can be applied before (IPC) or after (ischemic preconditioning) onset of the sustained episode of lethal ischemia, or even at the onset of myocardial reperfusion, which called IPostC . Furthermore, the protective stimulus can be applied by placing a blood-pressure cuff on an upper or lower limb to induce brief episodes of nonlethal ischemia and reperfusion (remote ischemic conditioning, RIC), as well as pharmacological conditioning is applied to clinical with elucidation of the signal-transduction pathways underlying ischemic conditioning . We will describe the role of mTOR in ischemic and pharmacological conditioning hereinafter (Table 1).
Accumulating evidences derived from experimental models and clinical patients show that mTOR plays an important role in the progression of IR injury [15, 16]. It is still controversial to clearly understand the role of mTOR signaling in reperfusion injury since both protective and toxic effects were observed in vivo and in vitro . Researchers have found both protective and toxic effects of mTOR signaling when using its inhibitor-rapamycin or transgenic animals [16, 18, 143, 158, 159]. The conflicted outcomes could be explained for five reasons: (i) mTORC1 and mTORC2 have different functions. mTORC1 presents both beneficial and detrimental effects on reperfusion injury while mTORC2 show mostly cardioprotective actions as its cellular survival functions [102, 160]; (ii) mTORC1 phosphorylation site is different. mTORC1 predominately phosphorylated the specific site encompassing 4E-BP1 that are rapamycin resistant as well as phosphorylated S6K1, which is rapamycin sensitive under conditions ; (iii) There are degrees of mTOR activation in the regulation of autophagy. Yu et al. revealed that mTOR signaling was inhibited during autophagy initially, but reactivated with prolonged autophagy, indicating that the progress was autophagy-dependent and required the degradation of autolysosomal products. In verse, the enhanced mTOR activity attenuated autophagy ; (iv) Loss-of-function animal models may have inescapable defects that may influence the results [162, 163]. Although mTOR’s role in reperfusion injury is controversial, a great many of experimental and clinical results proved that activation of mTOR thus inhibiting autophagy during reperfusion reduced IR injury, indicating that mTOR may be theoretically attractive as a therapeutic target.
Increasing evidences suggest that mTOR is deeply involved in IR injury of various organs and tissues, including heart, brain, kindey, liver and other organ or tissues [12, 85, 114, 146, 147]. The modulation of mTOR expression appears to be a promising strategy for attenuating IR injury. Autophagy that is under the control of mTOR contributes significantly to the degree of IR injury. However, effects of mTOR and autophagy activation in IR injury or conditioning progression are controversial, we have proposed possible reasons to explain the conflicted outcomes in potential future directions, including the variability in the experimental models and species, the methodology used to assess results, the severity of ischemia and its duration and the level of activation of autophagy . Many of experimental and clinical results revealed that it may play different roles depending on different stages. Activation not excessive autophagy via mTOR inhibition during ischemia while simulation of mTOR thus inhibiting autophagy during reperfusion respectively reduces IR injury. The impressive efficacy and safety of mTOR herald it as a promising agent for the treatment of IR injury. However, the interaction between mTOR and other important cellular processes of IR injury have not been fully explored, which deserves much attention in the future.