الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Myocardial infarction (MI) is the most serious form of ischemic heart diseases with a high mortality rate. It is characterized by myocardial necrosis and demonstrated as increased cardiac troponin levels.
Different types of cell death mechanisms occur in the ischemic heart throughout the disease progression, like autophagy, necrosis and apoptosis. Apoptosis is thought to be a mechanism that can remove the remains of tissue damage. Apoptosis could occur through intrinsic or extrinsic pathways, but both lead to mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, activation of caspases, DNA fragmentation and cell blebbing.
Mitochondrial alterations are prominently involved in the apoptosis and necrosis of cardio myocytes in the infarcted heart. Reactive oxygen species (ROS) are considered critical signalling particles that can result into oxidative damage to DNA, proteins, and lipids, along with the opening of the mitochondrial permeability transition pore (MPTP). MPT is considered as a consequence of oxidative damage to pre-existing membrane proteins. Lipid peroxidation produces unsaturated aldehydes such as acrolein and MDA, which have toxic effects and considered to be mediators of inflammation and vascular dysfunction due to their capability to produce protein and DNA adducts.
The primary goal of acute management of MI is to rapidly restore blood flow to the acutely occluded coronary artery, which can be attained medically or mechanically. In patients with hemodynamic stability, beta-blockers must be begun within the first 24 hours of the onset of chest discomfort to reduce myocardial oxygen consumption by decreasing heart rate, blood pressure and myocardial contractility.
Carvedilol (CAR) is a non-selective α1- and β-adrenoreceptor blocker. It showed a significant role in reducing morbidity and mortality in heart failure and post-acute MI patients. It has been shown to produce significant cardio protective effects in a variety of experimental models of cardiac ischemia, depending on its potent antioxidant and anti-apoptotic properties.
Due to the lack of perfect treatment strategies, the prevention of MI has received more attention in recent years. New studies report the beneficial role of consuming polyphenol-rich foods such as chlorogenic acid (CGA) in preventing myocardial infarction. CGA has a wide range of biological effects that may offer a non-invasive method for preventing or treating various chronic cardiovascular conditions.
In this context, the current work was carried out to investigate the possible cardio protective effects of chlorogenic acid alone and when used in combination with carvedilol therapy in acute myocardial infarction induced by isoproterenol (ISO) in experimental rats. Also, the study aims to understand the possible mechanisms of CGA and CRV effects on the oxidative stress, apoptosis and mitochondrial damage. The synthetic catecholamine medication isoproterenol (ISO), a beta-adrenergic agonist, has the ability to cause localised necrosis of the heart muscle by inflicting oxidative damage on the myocardium. The drug
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damages the heart by increasing mitochondrial ROS production, decreasing anti-oxidative capacity and altering mitochondrial respiratory chain function.
In our study, forty male albino rats weighing 200-250 g were used and randomly divided into the following experimental groups, each of 8 rats:
group I (Normal control): Rats in this group received gum acacia via oral intubation daily for 20 days and in addition, received 0.9% normal saline subcutaneously (S.C) on the 21st and 22nd days at a 24 hour interval. Then rats continued receiving gum acacia for 7 days.
group II (Positive control): which served as control to the CGA-prophylactic& CRV-treated rats. They received gum acacia daily for 20 days and in addition, they were subjected to induction of AMI using ISP dissolved in saline on the 21st and 22nd days at an interval of 24 hour. Four of them were sacrificed the next day as they served as control (IIa) to the CGA-prophylactic rats. While the other 4 rats continued to receive gum acacia for 7 days, then they were sacrificed as they served as control (IIb) to CRV-treated rats.
group III (ISP+CRV) carvedilol- treated group: Rats received gum acacia daily for 20 days, and in addition, they were subjected to induction of AMI on the 21st and 22nd days at an interval of 24 hours. Then rats received CRV 5 mg/ kg/day suspended in gum acacia for 7 days.
group IV (CGA + ISP) chlorogenic acid-prophylactic group: In this group, rats received a daily dose of CGA 40 mg/kg/day, suspended in 2% gum acacia, orally for 20 days, along with concurrent induction of MI on the 21st and 22nd days at an interval of 24 h.
group V (CGA + ISP+ CRV) CGA-prophylactic& CRV-treated group: Rats in this group received CGA suspended in gum acacia for 20 days, along with concurrent induction of MI on the 21st and 22nd days at an interval of 24 hours. Then rats received CRV for 7 days.
Blood samples were obtained 24 hours following the second (ISO) injection for rats in groups IIa & IV and sera were separated for measuring serum cardiac markers: aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and cardiac troponin I (c Tn I). The same procedures were done for rats of other groups, but after a 7-day treatment with CRV in groups III and V or gum acacia in groups I &IIb. Hearts of each group were excised and divided into parts for biochemical assessment of mitochondrial DNA copy number, α-ketoglutarate dehydrogenase (α-KGDH) and AMPK gene expression as a marker of exposure of cardiomyocyte to stress. In addition, BAX and Bcl-2 gene expression were assessed as markers of apoptosis.
Livers of each group were also excised and divided into portions for the determination of malondialdehyde (MDA) level, total glutathione (Tgsh), oxidized glutathione (GSSG), reduced glutathione (GSH) concentration and GSH/GSSG ratio as indicators of oxidative stress. Furthermore, histopathological examination using H&E on heart and liver tissues was conducted.
Results of the present work revealed that rats receiving CGA prophylaxis showed a significant decrease in serum cardiac markers and an improvement in redox state, as indicated by a significant decrease in MDA and GSSG levels with substantial rise in total glutathione, GSH levels and the GSH/GSSG ratio. Additionally, there was a considerable significant increase in the gene expression of α-KGDH and a non-significant increase in the gene expression of mtDNAcn, AMPK, and Bcl-2, however, BAX was dramatically decreased.
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Adding CRV at a dose of 5 mg/kg/day as therapy to CGA prophylaxis showed a more significant decrease in the injurious effect of ISO on the heart and liver tissues. There was a normalization of serum cardiac markers, amelioration of oxidative stress markers and a more significant increase in mtDNAcn, α-KGDH & AMPK gene expression. Also, an improvement in the anti-apoptotic effect of CGA was achieved, which evidenced by a significant increase in Bcl-2 gene expression.
Regarding the histopathological finding, when ISO was administrated the cardiac tissue displayed myocardial cell separation and inflammatory mononuclear cell infiltration. While in CRV-treated rats there were regular cardiac muscles and mild necrosis. In addition, CGA-prophylaxis rats showed less destructive myocytes and moderate cellular infiltration.
In contrast to the CRV-treated group that showed marked architecture restoration, the liver sections of ISO-induced AMI rats revealed a dilated, congested central vein with ruptured endothelial cell lining and a considerable number of inflammatory cells around it. In the same context, CGA prophylactic rats showed a less dilated central vein with mild inflammatory cells. Fortunately, the combined CGA prophylaxis + CRV-treated rats showed a completely preserved and restored histopathological picture of both myocardial and hepatic tissue as compared to each drug alone, supporting the cardioprotective and hepatoprotective effects of both CGA and CRV.
To our knowledge, this is the first study to combine CGA prophylaxis and CRV treatment in MI management, which appeared to be efficient regarding all the studied parameters. Taken together, this work provided evidence that this combination protocol could be promising for the cardio protective measures against MI.