1 Cellular Mechanisms Underlying Conditioning of the Heart Name

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2 Several mechanisms underlay the functioning of the heart. For instance, myocardial infarction entails the heart attack that occurs when blood flowing to a part of the heart undergoes blockage for couple of minutes or hours causing the heart muscle to be damaged. The essay addresses how the problem occurs as well as the symptoms and the risk factors of this ailment. Ischemia preconditioning refers to the natural mechanism that protects the body organs and especially the heart from deleterious impairments of the ischemic reperfusion injury. There are several causes and benefits of preconditioning where the essay. In this case, the essay also explains how ischemia occurs in both humans and animals. Mitochondria play a major role in protecting the heart from ischemia preconditioning injury. This will also be based on deeper details in the essay where the working of the protective mechanism of the mitochondria will be addressed. Other mechanisms including ischemic preconditioning (IPC), remote ischemic preconditioning (RIPC) and post ischemic conditioning also facilitate mechanisms for protecting the heart and other organs of the body from ischemic preconditioning injury (IPI). A study and experiment concerning the effect of ischemic preconditioning and remote preconditioning will also be conducted. Key words Remote ischemic preconditioning, ischemic preconditioning, small bowel transplantation, intestines, ischemia reperfusion injury, heme oxgynase Abbreviation RIPC- Remote ischemic preconditioning IPC- Ischemic preconditioning

3 SBT-Small bowel transplantation HO-1-Heme oxygenase-1 IRI-Ischemia preconditioning injury Myocardial infarction Causes Myocardial infarction entails a heart attack that occurs when blood flowing inside the heart is blocked resulting to damage of the heart muscle (Suzuki et al., 2012, p.454). Generally, major cases of myocardial infarction are caused by blood clotting that result to blockage of the coronary artery. Coronary arteries are responsible for transporting oxygen and blood in the heart. Therefore, in a case whereby blocking of the blood flow occurs, the heart lacks or suffers shortage of oxygen thus leading to death of the heart cell. Sometimes, cases of plaque build in the coronary artery walls. The plaque composes of other cells and cholesterol. According to research, heart attack is reported to occur when platelets of blood stick to plaque tears forming a blood clot which in return blocks the blood entering the heart. It is reported to be the common factor causing heart attacks in any incidences. Moreover, this slow plaque build up can cause the blocking of the coronary artery. The heart attack comes when one is asleep or taking some rest. Heart attack may also occur due to sudden increase of some physical activity. Moreover, heart attack may also occur when one is working in the cold weather or even after severe, emotional, sudden or even physical stress. Illness may also be a major cause of heart attack. Symptoms of mitochondria infarction

4 One of the symptoms of mitochondria infarction is the chest pain where the pain maybe experienced in part of the body. This pain may originate for the chest to the other organs of the body including arms and the neck (Alspach, 2012, p.10). Nausea is another symptom of mitochondria infarction. A troponin blood test might indicate some damage in the heart tissues thus indicating the presence of mitochondria infraction. Preconditioning Ischemia preconditioning Ischemia preconditioning (IP) entails heart exposure to short time frames of ischemia interspersed with normal perfusion time frames before the prolonged is introduced within a sixty minute preconditioning protocol. strong protection existed from the protocol which indicated resistance to reperfusion injury in a dogs heart from a research conducted in 1986 by Murray which also proved successful in humans and other animals as well (Saeki et al., 2011, p.858). Reduction of the infarct size is believed to occur only when optimal period regarding the test duration of ischemia is defined and often disappears if the ischemic time frame is prolonged. Preconditioned hearts demonstrates an intracellular release of enzymes and lesser infarct size and decreased arrhythmias at the same time protecting the contractile function. When Ischemia is introduced for more than 60-120 minutes after the protocol of preconditioning, protection tends to disappear but emerges after a period of one day and lasts for a period of 3 days. This initially is known as the second preconditioning window. Some drugs that activate numerous signaling pathways are believed to take part in mediating ischemia preconditioning often induce protection, therefore preconditioning is understood as a general term that covers any protocol introduced before protracted ischemia protecting the heart at the time of reperfusion

5 (Zimmerman et al., 2011, p.868). Post-preconditioning is another concept that nearly works under the same criteria as the ischemia precondition though they are far different. Ischemic Post-conditioning Ischemic post-conditioning is also known as stuttering reperfusion and is generally performed right after reperfusion in order to prevent reperfusion/ischemia injury in cerebral and myocardial infarction (Zimmerman et al., 2011, p.868). This concept has gone through some evolution whereby broad variety of triggers or stimuli can be used to induce the process and can as well be performed six hours after the occurrence of focal ischemia and 48 hours after the process of transient global Ischemia. The concept stems from gradual/partial reperfusion or ischemic preconditioning although research indicates that post-conditioning process was experimented earlier than gradual/partial reperfusion or preconditioning on myocardial ischemia research. The protective effects of ischemia post-conditioning are in some way similar to that of ischemia preconditioning. Both ischemic preconditioning and post-conditioning have evolved to the concept of being induced by a broad variety of triggers or stimuli. Minguet (Minguet et al., 2007, p.734) carried out and experiment to investigating protective effect of IPC (ischemic preconditioning) together with RIPC (remote ischemic preconditioning) against cold Ischemia in SBT (small bowel transplantation). Minguet (Minguet et al., 2007, p.734) found out that values of tissue injury were comparatively lower in the ischemia preconditioning and in remote ischemia preconditioning than it was noted on control groups, three hours after performing the small bowel transplantation where the protective effects against cold ischemia reperfusion injury diminished by twelve and twenty four hours after small bowel transplantation. Both remote ischemic preconditioning and ischemic

6 preconditioning were proved to fight against ischemia reperfusion injury after the rat small bowel transplantation in early phase. In this case, Heme oxygenase-1 would facilitate protection against cold ischemia reperfusion injury. Ischemia reperfusion injury generally occurs in the small intestine after the process of small bowel transplantation whereby it leads to endotoxemia, bacteria translocation, acute respiratory distress syndrome as well as multiple failure of the organ. Ischemia preconditioning protects both organs distally located situated against ischemic reperfusion injury and those in direct target of IPC. This results to a phenomenon known as the Remote Ischemia preconditioning (RIPC). Studies from the clinic in regard to remote ischemia preconditioning have been performed using the vascular surgery although none of the reports produced have ever addressed remote ischemic preconditioning having protective effects against cold ischemia preconditioning injury within the small intestines. The only beneficial effect of ischemic preconditioning and remote ischemic preconditioning is in relation to the induction of heat shock proteins (Hsp) (Piper & Dorado, 2009). Heme oxygenase -1 is generally induced for the protection of intestines in ischemic reperfusion injury as well as exotic shock models. therefore, the aim of conducting the study is identifying the protection level by RIPC and IPC against cold ischemic reperfusion injury with the use of rat small bowel transplantation model and to find out whether the same protective effect still apply to the induction of heme oxygenase-1. According to Zhe-Min Ding (Zhe-Min Ding et al., 2012, p.6090) unpaired students (t) test was used to perform the statistical analysis where the error bars were used to indicate the standard deviation. Setting of the statistical was in a threshold represented by p < 0.05 as used during the analysis. Effects of RIPC and IPC on cold ischemic preconditioning injury using small intestine graft

7 The small intestines indicated histopathologies at 3hours immediately after the Small bowel transplantation. The villi were extremely denuded within the control group but were preserved well in the RIPC and IPC groups. According to Minguet (Minguet et al., 2007, p.734) the small intestinal transplanted graft was protected for ischemic preconditioning injury in both RIPC and IPC groups at three and six hours after the small bowel transplantation (p < 0.005). Although protective effects were seen to disappear at twelve and one day after the SBT, in RIPC and IPC groups the park score was elevated slightly (Zhe-Min Ding et al., 2012, p.6090). The IPC optimal protective procedure remains unidentified although some reports compiled by different authors indicate an IPC of 10 minute cycle in the intestinal IRI of the rat. Generally, there exists no RIPC medicated defense against cold IRI in the intestines of rats. In numerous organs, multiple RIPC circles are better than single cycle. Although RIPC and IPC mechanisms are not understood yet, some mediators including NF-Kb, heat shock proteins and No are released. This study indicate that ALT, AST and LDH are lower in LIPC and IPC, 3 hours after performing the small bowel transplantation (SLB). RIPC and IPC protective effects appear spread on other organs within the recipient rat. IPC effect on heart is reported to spread through coronary affluent infusion. According to Minguet (Minguet et al., 2007, p.734), IPC protective period was categorized into multiple phases which included the late phase and early phase where the early protection phase against IRI comes in the timeframe between 1 to 3 hours after the process of reperfusion whereas late protection phase comes in 24 hours after the process of reperfusion and disappears 12 to 24 hours after small bowel transplantation. A relationship between the protective effect disappearance and reduction of HO-1 serum level exists. In essence, the study revealed that RIPC and IPC are better methods for shielding the organs from IRI without using special tools or

8 medication. However, more and elaborate study is required when determining effect of RIPC and IPC in humans. Damage during reperfusion Reperfusion is mostly associated with the burst related to reactive oxygen species (ROS) process of production although debate still exists about the source of ROS. Complex 3 and complex 1 of respiratory chain forms the reactive oxygen species although the NADPH oxidase and the xanthine oxidase are other probable sources of ROS (Saeki et al., 2011, p.857). Lack of oxygen in the respiratory chain and immediate exposure of the oxygen leads to partial reduction of the obiquinone to obisemiquinone. A reaction between oxygen and obisemiquinone may occur thus resulting to superoxide which in return reacts with superoxide dismutase producing hydrogen peroxide. Removal of the hydrogen peroxide is carried out by catalase or glutathione peroxidase although the presence of ferrous ions leads to formation of hydroxyl radical which is highly reactive through a process of Fenton reaction. Reactive oxygen species damage affects the mitochondrial proteins whereby this is seen in the weakened activity of the respiratory chain related to mitochondria separated from ischemia hearts. Therefore, the reactive oxygen species has some effects on the numerous components of the respiratory system especially for complex 3 and complex 1. Sulphur ions like aconitase are also affected by the inducement of damaged reactive oxygen species. Reactive oxygen species also leads to glutathione oxidation which may result to formation of mixed disulphide together with proteins. This kind of protein modification has some inhibitory effects on the ion pumps and thus exacerbates ATP deprivation effects towards ionic homeostasis. In addition, reactive oxygen species also results to peroxidation of unsaturated components of fatty acid in the phospholipids and generally cardiolipin of the inner membrane of mitochondria and finally leading to inhibition of the activity of respiratory chain.

9 Generally, elevated [Ca2+] together with the effects of reactive oxygen species contribute in transition of reversible to irreversible reperfusion injury and mitochondria are the victims of the agents (Saeki et al., 2011, p.859). Mitochondrial permeability transition pore The mitochondria have an impermeable inner membrane under the normal physiological state. Only a few selected ions and metabolites can be allowed by the membrane. This helps maintain the pH gradient and membrane potential which drive the ATP synthesis through an oxidative phosphorylation. Increased matrix calcium conditions mostly when accompanied by some oxidative stress, low concentrations of adenine nucleotide and high phosphate, an identified pore appears from the mitochondrial inner membrane which is known as the Mitochondrial permeability transition pore (MPTP) (Giaime et al., 2012, p.1).the regulation and properties of the pore are known to perform several functions. Opening of the pore grants passage to any molecule of greater than 1.5 kDa and causes disturbance to the permeability of the inner membrane (Giaime et al., 2012, p.1). This process results to some consequences. For instance, this permits movement of the unrestricted proton in the inner membrane which results to oxidative phosphorylation on becoming uncoupled. This enables translocation of the proton ATPase in a reversal direction as well as preventing ATP synthesis and hydrolyses ATP actively instead of synthesizing it. ATP concentration declines under these conditions thus leading to the disruption of the metabolic homoeostasis and ions together with degradative enzyme activation such as proteases, nucleases and phospholipases. The pore closure has to occur in order to avoid the changes from triggering irreversible damage in the cell which would eventually lead to necrotic death. Immediate depolarization would occur from a single pore opening in the mitochondria. This leads to opening of more pores opening in the same mitochondria because

10 mitochondrial permeability pore opening is generally activated by the process of depolarization. The mitochondria lives in a state of fully closed or opened. If the mitochondria is fully opened it is exposed to the risk of extensive swelling whereby this generally happens when all small weight of the molecules equilibrate in the inner membrane thus leaving more concentration of the matrix proteins and exerting some colloidal osmotic force resulting to water uptake and swelling of the matrix. However, cristae unfolding gives way to expansion that takes place in the matrix without inner membrane rapture, damage might occur on the outer membrane leading to protein release to the space of the inter-membrane including cytocrome c. Insulin receptors and inhibitors Insulin like-growth factor entails a protein found on the human cells surface (Hantouche et al., 2010, p.88). The insulin receptor is a kind of Trans membrane receptor generally activated by the insulin growth factor-1(IGF-1) hormone as well by a relative IGF-2 hormone (Hantouche et al., 2010, p.88). The insulin receptor is associated with the tyrosine kinase receptor class which mediates the IGF-1 effects and is a polypeptide protein hormone similar to insulin in molecular structure. The IGF-1serves the purpose of growth and has anabolic effects in the adults which means that it induces skeletal muscle hypertrophy together with other tissues of target (Hantouche et al., 2010, p.88). Organisms which lack or suffer shortage of IGF-1 receptor often experience immature deaths and implicate reduced body mass thus revealing how important the receptor is for growth as well as development. The insulin receptor which belongs to tyrosine kinase family arbitrates their activity by increasing phosphate groups to tyrosine on particular cell protein. Phosphate addition leads to cell signaling cascades and the resulting IGF-1activation is proliferation and survival within mitosis-competent cells as well as tissue growth such as cardiac muscle and skeletal muscle (Hantouche et al., 2010, p.88). The IGF-1R pathway plays

11 the role of development of limbs buds (Garofalo et al, 2011, p.2730). IGR-1R contributes towards mammary glands tissue development during lactation and pregnancy. The role of insulin receptor and inhibitors Cardio-protective effect of insulin Cardio-protective effect of insulin have been examined through different research where insulin growth factor (IGF-1) it was noted that IGF-1 reduced the myocardial injury. This is achieved through the method of creatine kinase loss. The insulin growth factor also led to reduction of the cardiac myeloperoxidase activity which is an accumulation of neutrophil index (Fuster et al., 2005, p.831). Ischemic reperfused immunohistochemical analysis of myocardial tissue implicated markedly amplified fragmentation of the DNA due as a result of programmed death of the cells which put in comparison with nonischemic myocardium. The Insulin Growth Factor increased myocyte apoptosis incidence after reperfusion and myocardial ischemia. Generally, the Insulin Growth Factor has been experimented which has led to the conclusion that it preserves or protects the ischemic myorcadium from the reperfusion injury using the cardiac myoctes reperfusion-induced apoptosis and the polymorphonuclear leukocyte-induced cardiac necrosis (Fuster et al., 2005, p.831). Role in insulin signaling The IGF-1R binds both the insulin receptor and the IGF1receptor. The IGF-1R appears a physiologic receptor whereby it attaches the IGF-1 at a higher affinity than the binding of the insulin receptor. The IGF-1 works like the insulin receptor whereby it belongs to the tyrosine kinase receptors (Garofalo et al, 2011, p.2730). This means that once this receptor signals, it causes addition of phosphate molecule on tyrosine.

12 Conclusion Insulin receptors and inhibitors take part insulin signaling where receptor signals cause addition of phosphate molecule on tyrosine. Moreover, the inhibitors and insulin receptors also have role in aging of mammals where Carollically restricted mammals which are old lose IGF-1R of nonimmunoreactive cells in higher numbers at the same time maintaining similar IGF-1R immunoreactive cell count. Ischemic preconditioning (IPC) is one technique or mechanism that protects the body organs from effect of the Ischemic preconditioning injury (IRI). Ischemia post conditioning (IRI) and remote ischemic preconditioning (RIPC) are other mechanisms which are believed to serve the same purpose as the Ischemic preconditioning (IPC) in protecting the body organs from ischemic preconditioning injury (IRI). The study has proved that both ischemic preconditioning (IPC) and remote ischemic preconditioning (RIPC) can be practiced in clinical research to determine the effect of both on human beings although this requires more studies.

13 References Alspach, J 2012, 'Acute Myocardial Infarction Without Chest Pain: A Life-Threatening Variant?', Critical Care Nurse, 32, 4, pp. 10-13, CINAHL Plus with Full Text. Garofalo, C., Manara, M., Nicoletti, G., Marino, M., Lollini, P., Astolfi, A., & ... Scotlandi, K. (2011). Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling. Oncogene, 30(24). Giaime, E, Yamaguchi, H, Gautier, C, Kitada, T, & Jie, S 2012, 'Loss of DJ-1 Does Not Affect Mitochondrial Respiration but Increases ROS Production and Mitochondrial Permeability Transition Pore Opening', Plos ONE, 7, 7, pp. Hantouche, C. M., Bitar, K. M., Nemer, G. M., Obeid, M. Y., Kadi, L. N., Der-Boghossian, A. H., & Bikhazi, A. B. (2010). Role of glucagon-like peptide-1 analogues on insulin receptor regulation in diabetic rat hearts. Canadian Journal Of Physiology & Pharmacology, 88(1), 54-63. Minguet G, Joris J, Lamy M. Preconditioning and protection against ischaemia-reperfusion in non-cardiac organs: a place for volatile anaesthetics?. European Journal Of Anaesthesiology (Cambridge University Press) [serial online]. September 2007;24(9):733. Piper, M., H. & Dorado, D., G. 2009. SPOTLIGHT ISSUE ON Cardiac Protection Cardiovasc Res. Volume 83(2).

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