Propofol Cardioprotection against Myocardial Ischemia- Reperfusion Injury: A Mechanistic Review
Xiaowen Mao1, Zhi-dong Ge1, Xiang Xie1, Qingquan Lian1*, and Zhengyuan Xia1,2
1Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; 2 Department of Anesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
Correspondence: firstname.lastname@example.org (Z.X.); email@example.com (Q.L.)
Mao X et al. Reactive Oxygen Species 1(3):178–188, 2016; ©2016 Cell Med Press
(Received: January 30, 2016; Revised: February 11, 2016; Accepted: February 11, 2016)
ABSTRACT | Reperfusion after prolonged ischemia is necessary to rescue injured hearts while it paradoxically worsens cardiac injury, a phenomenon termed myocardial ischemia-reperfusion injury (MIRI). Overproduction of reactive oxygen species, calcium overload, and inflammation contribute to the pathogenesis of MIRI. Propofol, a commonly used anesthetic with antioxidant property, has been shown to be cardioprotective in experimental studies and in some small clinical trials of cardiac surgery using cardiopulmonary bypass. However, its effectiveness of cardioprotection needs to be confirmed in large clinical trials, and the mechanisms of its action remain a focus of current research. The purpose of this review is to delineate and summarize the mechanism underlying propofol-mediated cardioprotection against MIRI.
KEYWORDS | Antioxidant; Cardioprotection; Myocardial ischemia reperfusion injury; Nitric oxide; Propofol; Protective survivor activating factor enhancement pathway; Reperfusion injury signaling kinase pathway
ABBREVIATIONS | CHD, coronary heart disease; HO-1, heme oxygenase-1; LPS, lipopolysaccharide; MIRI, myocardial ischemia-reperfusion injury; mPTP, mitochondrial permeability transition pore; NO, nitric oxide; RISK, reperfusion injury signaling kinase; NFκB, nuclear factor-kappa B; NOS, nitric oxide synthase; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; SAFE, protective survivor activating factor enhancement; TNFα, tumor necrosis factor-alpha
2. The Pathogenesis of Myocardial Ischemia-Reperfusion Injury (MIRI)
3. Structure and Features of Propofol
4. Propofol’s Non-Anesthetic Effects Make It a Cardioprotective Drug
4.1. Antioxidant Property
4.2. Nitric Oxide Induction
4.3. Relevant Pro-Survival Signaling Pathways
4.3.1. The Reperfusion Injury Signaling Kinase (RISK) Pathway
4.3.2. The Protective Survivor Activating Factor Enhancement (SAFE) Pathway
4.3.3. The Activation of NFκB
4.3.4. The Increase of Bcl-2 Content
5. Specific Challenges in Diabetes
The increasing death rate and considerable economic burden resulting from coronary heart disease (CHD) lead to an urgent need for therapeutic strategies for CHD. Therapy targeting the initial myocardial infarction subsequent to the ischemia is a main focus during CHD treatment. Early reperfusion is an absolute prerequisite for the survival of ischemic myocardium, while reperfusion per se paradoxically worsens cardiac injury.
The hypnotic agent propofol (2,6-diisopropyl-phenol) is widely used during the induction and maintenance of anesthesia. It is commonly used as an intravenous anesthetic in cardiac surgery and has been shown to attenuate myocardial dysfunction  and reduce infarct size  after prolonged ischemia. However, there is no systematic discussion about the effect and mechanism of propofol-mediated protection against ischemia-reperfusion-induced injury to the heart. This review is intended to provide background information and illustration relevant to propofol with particular reference to the heart. The review focuses on discussing the pathogenesis of post–ischemia-reperfusion injury in the heart and the possible signaling pathways involved in propofol-mediated cardiac protection.
2. THE PATHOGENESIS OF MYOCARDIAL ISCHEMIA-REPERFUSION INJURY (MIRI)
Myocardial ischemia initiates a range of cellular events, causing damage to the myocardium due to blood supply cutoff. Although reperfusion is essential for the cell to survive and to restore normal function, it paradoxically causes damage to the cell, which is called “ischemia-reperfusion injury”. The pathogenesis of MIRI has been comprehensively studied, and the underlying molecular mechanism is complicated. Oxidative stress, intracellular calcium overload, mitochondrial permeability transition pore (mPTP) opening, endoplasmic reticulum stress, and inflammation all contribute to MIRI [3–8]. Briefly, during ischemic period intracellular pH decreases due to the enhanced aerobic metabolism that also fosters the activity of the Na+/H+ exchanger and Na+/Ca2+ exchanger. During reperfusion, the Ca2+ overload occurs, and the excessive intracellular Ca2+ then subsequently causes mPTP opening, a commonly accepted pathway leading to cell apoptosis and necrosis. Moreover, reactive free radicals are abundantly generated and accumulated during ischemia-reperfusion, which can directly carboxylate protein and cause lipid peroxidation as well as DNA damage. In addition, reperfusion also triggers several pro-death kinases (e.g., c-Jun N-terminal kinases, Ca2+/calmodulin-dependent protein kinase, and p38 MAPK, among others) and induces inflammation . The activated kinases and recruited neutrophils during inflammation also facilitate mPTP opening , Ca2+ overload, and ROS generation . Thus, multiple factors along with the intimate interactions among them contribute to the pathogenesis of MIRI.
3. STRUCTURE AND FEATURES OF PROPOFOL
Propofol (structure shown in Figure 1), marketed as Diprivan, is a short-acting, intravenous anesthetic agent that was first introduced in the late 1980s. The currently available preparation of Diprivan contains 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25% glycerol as a tonicity-adjusting agent, and sodium hydroxide to adjust the pH. As propofol is not soluble in water, it is formulated in an oil-in-water emulsion and is highly opaque white. A water-soluble form of propofol, namely, fospropofol, has recently been developed and approved by the United States Food and Drug Administration in 2008. Fospropofol may not produce the pain at the injection site that often occurs with the traditional form of the drug.
4. PROPOFOL’S NON-ANESTHETIC EFFECTS MAKE IT A CARDIOPROTECTIVE DRUG
Propofol has been widely used in anesthetic induction and maintenance during surgery. Propofol acts as an excellent anesthetic agent because it exhibits several advantages. For example, it is controllable during administration, has quick onset and rapid emergence from general anesthesia, and exerts minimal side effects. Aside from its anesthetic features, propofol also exhibits notable non-anesthetic effects, which can be of therapeutic importance. Propofol contains a structure similar to phenol-based free radical scavengers and resembles the structure of a-tocopherol (vitamin E), a natural antioxidant [12–15]. Propofol was reported to inhibit lipid peroxidation induced by free radicals such as hydroxyl or ferryl radicals  and scavenge peroxynitrite . It was shown to also inhibit plasma Ca2+ influx [17, 18]. Propofol had a direct negative inotropic effect at a supra-clinical concentration, which was mediated by a decrease in available intracellular Ca2+ concentration . Moreover, propofol was able to inhibit inflammatory responses of cells treated with lipopolysaccharide (LPS) .
As propofol is commonly used in cardiac surgery, the above mentioned non-anesthetic features suggest that propofol could be a therapeutic alternative against MIRI. Indeed, in the past 30 years researchers have investigated propofol-mediated protection against MIRI in different models. Early in the 1990s, Ko et al. started  and several studies followed [22, 23] to examine the effects of propofol administration on MIRI. In both isolated rat heart model and in vivo dog model, propofol appeared to be protective against MIRI in a dose-dependent manner. Propofol attenuated myocardial mechanical dysfunction, metabolic derangement, and lipid peroxidation during reperfusion [21–23].
Since 2000, studies have switched from examining the phenomenon of propofol-mediated cardioprotection to investigating the underlying mechanism. Since propofol is a free radical scavenger and a plasma membrane calcium channel inhibitor, its influence on mitochondria was extensively studied [24–27]. Most recently, Lemoine et al. reported that during early post–hypoxic re-oxygenation period, the cardiomyocyte protection by propofol was mediated by mitochondrial adenosine triphosphate-sensitive potassium channel opening, nitric oxide synthase activation, and stimulation of mitochondrial respiratory chain complexes . Propofol-mediated reduction in 15-F2t-isoprostane content, a specific and reliable index of lipid peroxidation, was first discussed in 2003 by Xia et al. [29, 30]. The effects of propofol on neutrophil function [31, 32] and inflammatory response [33–35] were also studied. In the latest ten years, propofol-mediated cardioprotection in vivo [36, 37] and in clinical settings [38, 39] was extensively investigated. Furthermore, increasing studies were carried out recently regarding the comparison of propofol with other anesthetics (e.g., sevoflurane and desflurane) [35, 40] or propofol combination treatment with other drugs [41–43]. In the present review, the underlying mechanism proposed in the previous studies regarding propofol-mediated cardioprotection against MIRI along with the most updated challenges in this research area are presented.
4.1. Antioxidant Property
The antioxidant activity of propofol results partly from its phenolic chemical structure, because the hydroxyl group can release hydrogen and thereafter be converted into a less active radical by the resonance of the aromatic ring. Kokita et al. first reported in 1996 that propofol attenuated the adverse changes induced by reactive oxygen species (ROS) in the heart . Then the effect was verified in both in vitro and in vivo studies in 1998 . Propofol was shown to protect cells against oxidative stress and enhance the endogenous antioxidant capacity through lipid peroxidation inhibition in different models [45, 46]. In addition, propofol can react with peroxynitrite to form a phenoxyl radical, therefore demonstrating the property of peroxynitrite scavenging . Peroxynitrite, a potent and unstable ROS, can damage a wide array of molecules in cells, including DNA and protein. Acquaviva et al. demonstrated that propofol protected cultured astrocytes from peroxynitrite-mediated cytotoxicity, and the effect was partly mediated by induction of the heme oxygenase (HO)-1 pathway in a dose-dependent manner . Since that, the cytoprotective effect of propofol via upregulation of HO-1 has been studied in vitro and in vivo [49, 50]. The antioxidant property of propofol is substantiated by studies in a variety of cell types or organelles, such as neurons [51, 52], astrocytes [53–55], mitochondria [12, 56], and microsomes .
4.2. Nitric Oxide Induction
The cardioprotective actions of propofol may not be solely due to its antioxidant property. Nitric oxide (NO) is essentially produced by all cell types in the heart and is known to have profound effects on cardiac function. The synthesis of NO requires the participation of nitric oxide synthases (NOS), present in three isoforms: neuronal NOS (nNOS) and endothelial NOS (eNOS), which are calcium-dependent forms, and inducible NOS (iNOS), which is expressed upon stimulation by microbial or immunological stimuli [57–59]. In general, eNOS-derived NO plays an important role in maintaining coronary vasodilatory tone , inhibiting platelet aggregation , and the adhesion of neutrophils  and platelets [63, 64] under physiological conditions in the heart. Moreover, NO has negative inotropic and chronotropic effects on cardiomyocytes [65, 66]. Multiple studies demonstrated increased eNOS/NO upon propofol treatment of vascular endothelial cells [67, 68], which might account, at least partially, for propofol-mediated cardiovascular protection. On the other hand, propofol also affected NO-mediated activities under inflammation . As the direct participation of NOS is a fundamental step in NO synthesis, it is suggested that propofol may modify the activity of NOS, especially iNOS . Propofol increased constitutive NO production by human neutrophils, but inhibited NO production by iNOS in these cells . Abnormal high concentrations of NO are generally produced by iNOS and transformed into peroxynitrite when superoxide anion radicals are present. It was further reported that propofol had a direct inhibitory effect on iNOS, especially when iNOS was induced by LPS . Furthermore, it was revealed that in surgical patients treated with propofol, levels of pro-inflammatory mediators were reduced while anti-inflammatory mediators remained unchanged [70, 72–75]. Hence, propofol may have a dual effect on NO—it induces eNOS/NO, leading to cardioprotection and inhibits iNOS/NO, resulting in suppression of inflammatory injury.
4.3. Relevant Pro-Survival Signaling Pathways
4.3.1. The Reperfusion Injury Signaling Kinase (RISK) Pathway
Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is one of the key cellular pro-survival pathways central to the prevention of ischemia–reperfusion injury. A number of growth factors activate Akt through phosphorylation of its threonine-308 or serine-473 residue. Upon activation, Akt proceeds to regulate its downstream genes, such as nuclear factor-κB (NFkB), B-cell lymphoma-2 (Bcl-2) family, and eNOS, leading to anti-apoptotic effect [76, 77]. It was reported that propofol induced Akt and protected cardiac H9c2 cells from apoptotic injury in response to oxidative stress . Also, the enhancement of the PI3K/Akt pathway played a critical role in propofol-mediated protection against myocardial toxicity from doxorubicin .
4.3.2. The Protective Survivor Activating Factor Enhancement (SAFE) Pathway
The activation of the Janus tyrosine kinase (JAK)–signal transducer and activator of transcription 3 (STAT3) signaling pathway plays an important role in limiting MIRI. Activation of STAT3 has been reported to limit cardiomyocyte apoptosis in rat models of myocardial infarction . STAT3 also has been confirmed to exert an anti-apoptotic effect in cultured neonatal rat cardiac myocytes subjected to anoxia . Propofol was shown to activate STAT3 in various models. Propofol improved cardiac function and ameliorated hyperglycemia-induced cardiomyocyte hypertrophy and apoptosis via activating HO-1/STAT3 pathway . It was also suggested that propofol not only induced JAK2/STAT3, but also PI3K/Akt activation in cultured H9c2 cells in a concentration-dependent manner .
4.3.3. The Activation of NFκB
NFκB is another transcription factor involved in myocardial ischemia-reperfusion injury and cardioprotection. NFκB is activated upon stimulation by various factors, such as tumor necrosis factor-alpha (TNFα), but it can in turn increase the transcriptional level of cell survival genes . Thus, it is suggested that NFκB might act differently under different conditions. It was reported that activation of NFκB could transcriptionally induce Bcl-2 expression in pancreatic cells . Propofol could induce the perinuclear translocation of NFκB p65 subunit and enhance cell survival in cardiac H9c2 cells . On the other hand, propofol could also reduce LPS-induced inflammatory responses in macrophages by inhibiting ROS-induced NFκB activation . Propofol inhibited hepatic NFκB activation, resulting in decreased production of the pro-inflammatory cytokines TNFα and interleukin-6 . The different performance of NFκB under propofol administration may be attributed to the different roles that propofol may play in cell protection. Under normal conditions, propofol tended to induce concomitant STAT3 and NFκB activation manifested as enhanced nuclear translocation and facilitate the crosstalk between the SAFE and the RISK pathways . In contrast, when facing exacerbated inflammation, propofol conferred its anti-inflammatory effect and reduced NFκB content [88, 89].
4.3.4. The Increase of Bcl-2 Content
Increase in the transcription of Bcl-2 helps prevent cardiomyocyte apoptosis, which is an important mechanism of many anti-MIRI therapies [90, 91]. When activated, Bcl-2 localized to the intracellular sites of ROS generation and functioned in an antioxidant pathway to prevent cell apoptosis . Li et al. reported that propofol showed neuroprotective effects against neuronal apoptosis by increasing Bcl-2 expression . Propofol, at concentrations ≥12 μM, significantly and concentration-dependently ameliorated TNFα-induced Bcl-2 reduction and enhanced NO production . Although propofol may regulate Bcl-2 expression through Akt, the drug may also modulate Bcl-2 gene expression through Akt-independent pathway .
5. SPECIFIC CHALLENGES IN DIABETES
The mortality rate of diabetic patients suffering from acute myocardial infarction after MIRI is much higher than that in patients without diabetes . In addition, diabetic patients exhibit worse recovery after acute myocardial infarction . The exacerbation of oxidative stress and reduction of endogenous antioxidant capacity together with the impairment of protective signaling pathways related to the activation of STAT3 and Akt contribute to the increased post–ischemic myocardial injury in diabetes after prolonged ischemic insult. The most recent study by Ansley et al. first demonstrated that propofol might be a preemptive intraoperative cardioprotectant for patients with type 2 diabetes under conditions of normothermic cardiopulmonary bypass and blood cardioplegic arrest, and the mechanism was related to Bcl-2 activation . However, the detailed underlying mechanism especially whether propofol confers cardioprotection in diabetes through its antioxidant capacity remains to be further explored.
In summary, propofol is a short-acting intravenous anesthetic agent that causes few side effects and thus has a favorably safety profile. Propofol possesses antioxidant property and causes activation of multiple pro-survival signaling pathways. It is likely that the non-anesthetic effects of propofol, including the signaling pathways it affects (Figure 1), may make the drug a potential cardioprotective agent in clinical practice. However, more investigations regarding the clinical implications and mechanism of propofol-mediated cardioprotection are needed in order to further establish its safety and efficiency.
FIGURE 1. Summary of the proposed mechanism by which propofol confers cardioprotection against myocardial ischemia-reperfusion injury (MIRI). Propofol ameliorates MIRI-induced oxidative stress and enhances cardioprotective nitric oxide production by eNOS. Propofol also can activate phosphoinositide 3-kinase (PI3K)/Akt signaling pathway as well as the Janus tyrosine kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Activation of JAK/STAT3 may inhibit mitochondrial permeability transition pore (mPTP) opening. Moreover, by activating NFκB and Bcl-2 propofol reduces cardiomyocyte apoptosis. It should be noted that ROS may act as a double-edged sword. On the one side, ROS at high levels can directly cause apoptosis. On the other side, ROS at low levels may cause activation of NF-κB, leading to suppression of apoptosis. It is speculated that propofol might help control ROS at a relatively low level via its antioxidant property (not shown in the scheme) to permit NF-κB activation without directly causing apoptosis. It is also noteworthy that NO derived from eNOS is typically cardioprotective whereas NO derived from iNOS usually causes detrimental effects. Hence, the intimate interactions among the diverse factors depicted in the scheme appear to account for propofol-mediated cardioprotection in MIRI.
The authors’ work was supported by Zhejiang Provincial Top Priority First Level Discipline grant, China. We thank Shenzhen IVY-Valued Biotechnology Co. Ltd. for editorial assistance.
- Kokita N, Hara A. Propofol attenuates hydrogen peroxide-induced mechanical and metabolic derangements in the isolated rat heart. Anesthesiology 1996; 84(1):117–27.
- Ebel D, Schlack W, Comfere T, Preckel B, Thamer V. Effect of propofol on reperfusion injury after regional ischaemia in the isolated rat heart. Br J Anaesth 1999; 83(6):903–8.
- Semenza GL. Cellular and molecular dissection of reperfusion injury: ROS within and without. Circ Res 2000; 86(2):117–8.
- Hess ML, Manson NH. Molecular oxygen: friend and foe. The role of the oxygen free radical system in the calcium paradox, the oxygen paradox and ischemia/reperfusion injury. J Mol Cell Cardiol 1984; 16(11):969–85.
- Zhang PL, Lun M, Teng J, Huang J, Blasick TM, Yin L, et al. Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Ann Clin Lab Sci 2004; 34(4):449–57.
- McCord JM. Oxygen-derived radicals: a link between reperfusion injury and inflammation. Fed Proc 1987; 46(7):2402–6.
- Wang XX, Wang XL, Tong MM, Gan L, Chen H, Wu SS, et al. SIRT6 protects cardiomyocytes against ischemia/reperfusion injury by augmenting FoxO3alpha-dependent antioxidant defense mechanisms. Basic Res Cardiol 2016; 111(2):13. doi: 10.1007/s00395-016-0531-z.
- Chen M, Zhou X, Yu L, Liu Q, Sheng X, Wang Z, et al. Low-level vagus nerve stimulation attenuates myocardial ischemic reperfusion injury by antioxidative stress and antiapoptosis reactions in canines. J Cardiovasc Electrophysiol 2016; 27(2):224–31. doi: 10.1111/jce.12850.
- Lejay A, Fang F, John R, Van JA, Barr M, Thaveau F, et al. Ischemia reperfusion injury, ischemic conditioning and diabetes mellitus. J Mol Cell Cardiol 2015; 91:11–22. doi: 10.1016/j.yjmcc.2015.12.020.
- Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 2012; 298:229–317. doi: 10.1016/B978-0-12-394309-5.00006-7.
- Morgan MJ, Kim YS, Liu ZG. TNFalpha and reactive oxygen species in necrotic cell death. Cell Res 2008; 18(3):343–9. doi: 10.1038/cr.2008.31.
- Eriksson O, Pollesello P, Saris NE. Inhibition of lipid peroxidation in isolated rat liver mitochondria by the general anaesthetic propofol. Biochem Pharmacol 1992; 44(2):391–3.
- Murphy PG, Myers DS, Davies MJ, Webster NR, Jones JG. The antioxidant potential of propofol (2,6-diisopropylphenol). Br J Anaesth 1992; 68(6):613–8.
- Murphy PG, Bennett JR, Myers DS, Davies MJ, Jones JG. The effect of propofol anaesthesia on free radical-induced lipid peroxidation in rat liver microsomes. Eur J Anaesthesiol 1993; 10(4):261–6.
- Green TR, Bennett SR, Nelson VM. Specificity and properties of propofol as an antioxidant free radical scavenger. Toxicol Appl Pharmacol 1994; 129(1):163–9. doi: 10.1006/taap.1994.1240.
- Mathy-Hartert M, Deby-Dupont G, Hans P, Deby C, Lamy M. Protective activity of propofol, Diprivan and intralipid against active oxygen species. Mediators Inflamm 1998; 7(5):327–33. doi: 10.1080/09629359890848.
- Buljubasic N, Marijic J, Berczi V, Supan DF, Kampine JP, Bosnjak ZJ. Differential effects of etomidate, propofol, and midazolam on calcium and potassium channel currents in canine myocardial cells. Anesthesiology 1996; 85(5):1092–9.
- Li YC, Ridefelt P, Wiklund L, Bjerneroth G. Propofol induces a lowering of free cytosolic calcium in myocardial cells. Acta Anaesthesiol Scand 1997; 41(5):633–8.
- Kanaya N, Murray PA, Damron DS. Propofol and ketamine only inhibit intracellular Ca2+ transients and contraction in rat ventricular myocytes at supraclinical concentrations. Anesthesiology 1998; 88(3):781–91.
- Ma L, Wu X, Chen W, Fujino Y. Propofol has anti-inflammatory effects on alveolar type II epithelial cells. Acta Anaesthesiol Scand 2010; 54(3):362–9. doi: 10.1111/j.1399-6576.2009.02127.x.
- Ko SH, Yu CW, Lee SK, Choe H, Chung MJ, Kwak YG, et al. Propofol attenuates ischemia-reperfusion injury in the isolated rat heart. Anesth Analg 1997; 85(4):719–24.
- Kokita N, Hara A, Abiko Y, Arakawa J, Hashizume H, Namiki A. Propofol improves functional and metabolic recovery in ischemic reperfused isolated rat hearts. Anesth Analg 1998; 86(2):252–8.
- Yoo KY, Yang SY, Lee J, Im WM, Jeong CY, Chung SS, et al. Intracoronary propofol attenuates myocardial but not coronary endothelial dysfunction after brief ischaemia and reperfusion in dogs. Br J Anaesth 1999; 82(1):90–6.
- Javadov SA, Lim KH, Kerr PM, Suleiman MS, Angelini GD, Halestrap AP. Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc Res 2000; 45(2):360–9.
- Kajimoto M, Atkinson DB, Ledee DR, Kayser EB, Morgan PG, Sedensky MM, et al. Propofol compared with isoflurane inhibits mitochondrial metabolism in immature swine cerebral cortex. J Cereb Blood Flow Metab 2014; 34(3):514–21. doi: 10.1038/jcbfm.2013.229.
- Liu Q, Yao JY, Qian C, Chen R, Li XY, Liu SW, et al. Effects of propofol on ischemia-induced ventricular arrhythmias and mitochondrial ATP-sensitive potassium channels. Acta Pharmacol Sin 2012; 33(12):1495–501. doi: 10.1038/aps.2012.86.
- Jovic M, Stancic A, Nenadic D, Cekic O, Nezic D, Milojevic P, et al. Mitochondrial molecular basis of sevoflurane and propofol cardioprotection in patients undergoing aortic valve replacement with cardiopulmonary bypass. Cell Physiol Biochem 2012; 29(1–2):131–42. doi: 10.1159/000337594.
- Lemoine S, Zhu L, Gress S, Gerard JL, Allouche S, Hanouz JL. Mitochondrial involvement in propofol-induced cardioprotection: an in vitro study in human myocardium. Exp Biol Med (Maywood) 2016. doi: 10.1177/1535370215622586.
- Xia Z, Godin DV, Chang TK, Ansley DM. Dose-dependent protection of cardiac function by propofol during ischemia and early reperfusion in rats: effects on 15-F2t-isoprostane formation. Can J Physiol Pharmacol 2003; 81(1):14–21. doi: 10.1139/y02-170.
- Xia Z, Godin DV, Ansley DM. Propofol enhances ischemic tolerance of middle-aged rat hearts: effects on 15-F2t-isoprostane formation and tissue antioxidant capacity. Cardiovasc Res 2003; 59(1):113–21.
- Szekely A, Heindl B, Zahler S, Conzen PF, Becker BF. Nonuniform behavior of intravenous anesthetics on postischemic adhesion of neutrophils in the guinea pig heart. Anesth Analg 2000; 90(6):1293–300.
- Corcoran TB, Engel A, Sakamoto H, O’Shea A, O’Callaghan-Enright S, Shorten GD. The effects of propofol on neutrophil function, lipid peroxidation and inflammatory response during elective coronary artery bypass grafting in patients with impaired ventricular function. Br J Anaesth 2006; 97(6):825–31. doi: 10.1093/bja/ael270.
- Samir A, Gandreti N, Madhere M, Khan A, Brown M, Loomba V. Anti-inflammatory effects of propofol during cardiopulmonary bypass: a pilot study. Ann Card Anaesth 2015; 18(4):495–501. doi: 10.4103/0971-9784.166451.
- Baki ED, Aldemir M, Kokulu S, Koca HB, Ela Y, Sivaci RG, et al. Comparison of the effects of desflurane and propofol anesthesia on the inflammatory response and S100b protein during coronary artery bypass grafting. Inflammation 2013; 36(6):1327–33. doi: 10.1007/s10753-013-9671-6.
- Xia WF, Liu Y, Zhou QS, Tang QZ, Zou HD. Comparison of the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery. Yonsei Med J 2011; 52(2):326–32. doi: 10.3349/ymj.2011.52.2.326.
- Sun HY, Xue FS, Xu YC, Li CW, Xiong J, Liao X, et al. Propofol improves cardiac functional recovery after ischemia-reperfusion by upregulating nitric oxide synthase activity in the isolated rat hearts. Chin Med J (Engl) 2009; 122(24):3048–54.
- Lin C, Sui H, Gu J, Yang X, Deng L, Li W, et al. Effect and mechanism of propofol on myocardial ischemia reperfusion injury in type 2 diabetic rats. Microvasc Res 2013; 90:162–8. doi: 10.1016/j.mvr.2013.08.002.
- Lurati Buse GA, Schumacher P, Seeberger E, Studer W, Schuman RM, Fassl J, et al. Randomized comparison of sevoflurane versus propofol to reduce perioperative myocardial ischemia in patients undergoing noncardiac surgery. Circulation 2012; 126(23):2696–704. doi: 10.1161/CIRCULATIONAHA.112.126144.
- Soro M, Gallego L, Silva V, Ballester MT, Llorens J, Alvarino A, et al. Cardioprotective effect of sevoflurane and propofol during anaesthesia and the postoperative period in coronary bypass graft surgery: a double-blind randomised study. Eur J Anaesthesiol 2012; 29(12):561–9. doi: 10.1097/EJA.0b013e3283560aea.
- Yao YT, Li LH. Sevoflurane versus propofol for myocardial protection in patients undergoing coronary artery bypass grafting surgery: a meta-analysis of randomized controlled trials. Chin Med Sci J 2009; 24(3):133–41.
- Azeredo MA, Azeredo LA, Eleutherio EC, Schanaider A. Propofol and N-acetylcysteine attenuate oxidative stress induced by intestinal ischemia/reperfusion in rats: protein carbonyl detection by immunoblotting. Acta Cir Bras 2008; 23(5):425–8.
- Oksuz H, Senoglu N, Yasim A, Turut H, Tolun F, Ciralik H, et al. Propofol with N-acetylcysteine reduces global myocardial ischemic reperfusion injury more than ketamine in a rat model. J Invest Surg 2009; 22(5):348–52.
- Law-Koune JD, Raynaud C, Liu N, Dubois C, Romano M, Fischler M. Sevoflurane-remifentanil versus propofol-remifentanil anesthesia at a similar bispectral level for off-pump coronary artery surgery: no evidence of reduced myocardial ischemia. J Cardiothorac Vasc Anesth 2006; 20(4):484–92. doi: 10.1053/j.jvca.2005.08.001.
- Ansley DM, Lee J, Godin DV, Garnett ME, Qayumi AK. Propofol enhances red cell antioxidant capacity in swine and humans. Can J Anaesth 1998; 45(3):233–9.
- Hans P, Deby-Dupont G, Deby C, Pieron F, Verbesselt R, Franssen C, et al. Increase in antioxidant capacity of plasma during propofol anesthesia. J Neurosurg Anesthesiol 1997; 9(3):234–6.
- Stratford N, Murphy P. Antioxidant activity of propofol in blood from anaesthetized patients. Eur J Anaesthesiol 1998; 15(2):158–60.
- Mathy-Hartert M, Mouithys-Mickalad A, Kohnen S, Deby-Dupont G, Lamy M, Hans P. Effects of propofol on endothelial cells subjected to a peroxynitrite donor (SIN-1). Anaesthesia 2000; 55(11):1066–71.
- Acquaviva R, Campisi A, Murabito P, Raciti G, Avola R, Mangiameli S, et al. Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: an alternative protective mechanism. Anesthesiology 2004; 101(6):1363–71.
- Liang C, Cang J, Wang H, Xue Z. Propofol attenuates cerebral ischemia/reperfusion injury partially using heme oxygenase-1. J Neurosurg Anesthesiol 2013; 25(3):311–6. doi: 10.1097/ANA.0b013e31828c6af5.
- Liang C, Xue Z, Wang H, Li P. Propofol upregulates heme oxygenase-1 through activation of ERKs in human umbilical vein endothelial cells under oxidative stress conditions. J Neurosurg Anesthesiol 2011; 23(3):229–35. doi: 10.1097/ANA.0b013e31821c007f.
- Kochs E, Hoffman WE, Werner C, Thomas C, Albrecht RF, Schulte am Esch J. The effects of propofol on brain electrical activity, neurologic outcome, and neuronal damage following incomplete ischemia in rats. Anesthesiology 1992; 76(2):245–52.
- Yamasaki T, Nakakimura K, Matsumoto M, Xiong L, Ishikawa T, Sakabe T. Effects of graded suppression of the EEG with propofol on the neurological outcome following incomplete cerebral ischaemia in rats. Eur J Anaesthesiol 1999; 16(5):320–9.
- Sitar SM, Hanifi-Moghaddam P, Gelb A, Cechetto DF, Siushansian R, Wilson JX. Propofol prevents peroxide-induced inhibition of glutamate transport in cultured astrocytes. Anesthesiology 1999; 90(5):1446–53.
- Bevensee MO, Weed RA, Boron WF. Intracellular pH regulation in cultured astrocytes from rat hippocampus. I. Role of HCO3ˉ. J Gen Physiol 1997; 110(4):453–65.
- Lascola C, Kraig RP. Astroglial acid-base dynamics in hyperglycemic and normoglycemic global ischemia. Neurosci Biobehav Rev 1997; 21(2):143–50.
- Musacchio E, Rizzoli V, Bianchi M, Bindoli A, Galzigna L. Antioxidant action of propofol on liver microsomes, mitochondria and brain synaptosomes in the rat. Pharmacol Toxicol 1991; 69(1):75–7.
- Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF. Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. Proc Natl Acad Sci USA 1991; 88(17):7773–7.
- Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol 1992; 105(3):575–80.
- Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell SW, et al. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci USA 1993; 90(20):9730–4.
- McGowan FX, Jr., Davis PJ, del Nido PJ, Sobek M, Allen JW, Downing SE. Endothelium-dependent regulation of coronary tone in the neonatal pig. Anesth Analg 1994; 79(6):1094–101.
- Radomski MW, Palmer RM, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987; 92(3):639–46.
- Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991; 88(11):4651–5.
- Groves PH, Lewis MJ, Cheadle HA, Penny WJ. SIN-1 reduces platelet adhesion and platelet thrombus formation in a porcine model of balloon angioplasty. Circulation 1993; 87(2):590–7.
- Radomski MW, Palmer RM, Moncada S. Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987; 2(8567):1057–8.
- Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257(5068):387–9.
- Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA 1993; 90(1):347–51.
- Wang B, Luo T, Chen D, Ansley DM. Propofol reduces apoptosis and up-regulates endothelial nitric oxide synthase protein expression in hydrogen peroxide-stimulated human umbilical vein endothelial cells. Anesth Analg 2007; 105(4):1027–33, table of contents. doi: 10.1213/01.ane.0000281046.77228.91.
- Wang L, Jiang W. Propofol induces endothelial nitric oxide synthase phosphorylation and activation in human umbilical vein endothelial cells by inhibiting protein kinase C delta expression. Eur J Anaesthesiol 2010; 27(3):258–64. doi: 10.1097/EJA.0b013e3283311193.
- Liu YC, Chang AY, Tsai YC, Chan JY. Differential protection against oxidative stress and nitric oxide overproduction in cardiovascular and pulmonary systems by propofol during endotoxemia. J Biomed Sci 2009; 16:8. doi: 10.1186/1423-0127-16-8.
- Gonzalez-Correa JA, Cruz-Andreotti E, Arrebola MM, Lopez-Villodres JA, Jodar M, De La Cruz JP. Effects of propofol on the leukocyte nitric oxide pathway: in vitro and ex vivo studies in surgical patients. Naunyn Schmiedebergs Arch Pharmacol 2008; 376(5):331–9. doi: 10.1007/s00210-007-0220-4.
- Liu MC, Tsai PS, Yang CH, Liu CH, Chen CC, Huang CJ. Propofol significantly attenuates iNOS, CAT-2, and CAT-2B transcription in lipopolysaccharide-stimulated murine macrophages. Acta Anaesthesiol Taiwan 2006; 44(2):73–81.
- Concas A, Santoro G, Serra M, Sanna E, Biggio G. Neurochemical action of the general anaesthetic propofol on the chloride ion channel coupled with GABAA receptors. Brain Res 1991; 542(2):225–32.
- Delogu G, Antonucci A, Signore M, Marandola M, Tellan G, Ippoliti F. Plasma levels of IL-10 and nitric oxide under two different anaesthesia regimens. Eur J Anaesthesiol 2005; 22(6):462–6.
- Helmy SA, Al-Attiyah RJ. The immunomodulatory effects of prolonged intravenous infusion of propofol versus midazolam in critically ill surgical patients. Anaesthesia 2001; 56(1):4–8.
- Kudoh A, Katagai H, Takazawa T. Plasma inflammatory cytokine response to surgical trauma in chronic depressed patients. Cytokine 2001; 13(2):104–8. doi: 10.1006/cyto.2000.0802.
- Matsui T, Rosenzweig A. Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J Mol Cell Cardiol 2005; 38(1):63–71. doi: 10.1016/j.yjmcc.2004.11.005.
- Amaravadi R, Thompson CB. The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 2005; 115(10):2618–24. doi: 10.1172/JCI26273.
- Wang B, Shravah J, Luo H, Raedschelders K, Chen DD, Ansley DM. Propofol protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via Akt activation and Bcl-2 up-regulation. Biochem Biophys Res Commun 2009; 389(1):105–11. doi: 10.1016/j.bbrc.2009.08.097.
- Sun X, Gu J, Chi M, Li M, Lei S, Wang G. Activation of PI3K-Akt through taurine is critical for propofol to protect rat cardiomyocytes from doxorubicin-induced toxicity. Can J Physiol Pharmacol 2014; 92(2):155–61. doi: 10.1139/cjpp-2013-0246.
- Negoro S, Kunisada K, Tone E, Funamoto M, Oh H, Kishimoto T, et al. Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc Res 2000; 47(4):797–805.
- Stephanou A, Brar BK, Knight RA, Latchman DS. Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters. Cell Death Differ 2000; 7(3):329–30. doi: 10.1038/sj.cdd.4400656.
- Xu J, Li H, Irwin MG, Xia ZY, Mao X, Lei S, et al. Propofol ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction via heme oxygenase-1/signal transducer and activator of transcription 3 signaling pathway in rats. Crit Care Med 2014; 42(8):e583–94. doi: 10.1097/CCM.0000000000000415.
- Shravah J, Wang B, Pavlovic M, Kumar U, Chen DD, Luo H, et al. Propofol mediates signal transducer and activator of transcription 3 activation and crosstalk with phosphoinositide 3-kinase/AKT. JAKSTAT 2014; 3:e29554. doi: 10.4161/jkst.29554.
- Chen YJ, Chang LS. NFkappaB- and AP-1-mediated DNA looping regulates matrix metalloproteinase-9 transcription in TNF-alpha-treated human leukemia U937 cells. Biochim Biophys Acta 2015; 1849(10):1248–59. doi: 10.1016/j.bbagrm.2015.07.016.
- Galante JM, Mortenson MM, Bowles TL, Virudachalam S, Bold RJ. ERK/BCL-2 pathway in the resistance of pancreatic cancer to anoikis. J Surg Res 2009; 152(1):18–25. doi: 10.1016/j.jss.2008.05.017.
- Hsing CH, Lin MC, Choi PC, Huang WC, Kai JI, Tsai CC, et al. Anesthetic propofol reduces endotoxic inflammation by inhibiting reactive oxygen species-regulated Akt/IKKbeta/NF-kappaB signaling. PLoS One 2011; 6(3):e17598. doi: 10.1371/journal.pone.0017598.
- Song XM, Wang YL, Li JG, Wang CY, Zhou Q, Zhang ZZ, et al. Effects of propofol on pro-inflammatory cytokines and nuclear factor kappaB during polymicrobial sepsis in rats. Mol Biol Rep 2009; 36(8):2345–51. doi: 10.1007/s11033-009-9456-z.
- Zhou CH, Zhu YZ, Zhao PP, Xu CM, Zhang MX, Huang H, et al. Propofol Inhibits Lipopolysaccharide-Induced inflammatory responses in spinal astrocytes via the Toll-like receptor 4/myd88-dependent nuclear factor-kappaB, extracellular signal-regulated protein kinases1/2, and p38 mitogen-activated protein kinase pathways. Anesth Analg 2015; 120(6):1361–8. doi: 10.1213/ANE.0000000000000645.
- Zhang J, Jiang W, Zuo Z. Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor kappaB. Neuroscience 2014; 261:1–10. doi: 10.1016/j.neuroscience.2013.12.034.
- Raphael J, Abedat S, Rivo J, Meir K, Beeri R, Pugatsch T, et al. Volatile anesthetic preconditioning attenuates myocardial apoptosis in rabbits after regional ischemia and reperfusion via Akt signaling and modulation of Bcl-2 family proteins. J Pharmacol Exp Ther 2006; 318(1):186–94. doi: 10.1124/jpet.105.100537.
- Hattori R, Maulik N, Otani H, Zhu L, Cordis G, Engelman RM, et al. Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol 2001; 33(11):1929–36. doi: 10.1006/jmcc.2001.1456.
- Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993; 75(2):241–51.
- Li J, Han B, Ma X, Qi S. The effects of propofol on hippocampal caspase-3 and Bcl-2 expression following forebrain ischemia-reperfusion in rats. Brain Res 2010; 1356:11–23. doi: 10.1016/j.brainres.2010.08.012.
- Luo T, Xia Z, Ansley DM, Ouyang J, Granville DJ, Li Y, et al. Propofol dose-dependently reduces tumor necrosis factor-alpha-induced human umbilical vein endothelial cell apoptosis: effects on Bcl-2 and Bax expression and nitric oxide generation. Anesth Analg 2005; 100(6):1653–9. doi: 10.1213/01.ANE.0000150945.95254.D8.
- Alegria JR, Miller TD, Gibbons RJ, Yi QL, Yusuf S, Collaborative Organization of RheothRx Evaluation Trial I. Infarct size, ejection fraction, and mortality in diabetic patients with acute myocardial infarction treated with thrombolytic therapy. Am Heart J 2007; 154(4):743–50. doi: 10.1016/j.ahj.2007.06.020.
- Malmberg K, Ryden L. Myocardial infarction in patients with diabetes mellitus. Eur Heart J 1988; 9(3):259–64.
- Ansley DM, Raedschelders K, Choi PT, Wang B, Cook RC, Chen DD. Propofol cardioprotection for on-pump aortocoronary bypass surgery in patients with type 2 diabetes mellitus (PRO-TECT II): a phase 2 randomized-controlled trial. Can J Anaesth 2015. doi: 10.1007/s12630-015-0580-z.