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Title: The Roles of cell death on heart pathologies after Cardiac Ischemia/Reperfusion injury in rats
Other Titles: บทบาทของตัวยับยั้งการตายของเซลล์ต่อการเกิดพยาธิสภาพในหัวใจ ภายหลังการเกิดภาวะกล้ามเนื้อหัวใจขาดเลือดแล้วมีเลือดมาหล่อเลี้ยง
Authors: Luo, Ying
Authors: Nipon Chattipakorn
Arintaya Phrommintikul
Nattayaporn Apaijai
Luo, Ying
Keywords: Acute myocardial infarction
Issue Date: Mar-2022
Publisher: Chiang Mai : Graduate School, Chiang Mai University
Abstract: Acute myocardial infarction (AMI) is the leading cause of mortality worldwide. Coronary artery occlusion is known as the common cause of myocardial ischemia. The timely restore blood supply for the ischemic region is the most effective treatment strategy. Unfortunately, ischemia/reperfusion (I/R) injury subsequent causes further damage to the ischemic myocardium, leading to an expansion of myocardial infarction and cardiac dysfunction. Therefore, reperfusion injury substantially impacts the survival and prognosis of AMI patients who have accepted reperfusion therapy. The magnitude of the myocardial infarction is mainly determined by the severity of cell death. The growing evidence suggest that various forms of cell death are involved in cardiac I/R injury including apoptosis, necroptosis, and ferroptosis. Furthermore, inhibitors of apoptosis, necroptosis, and ferroptosis have been demonstrated the protective effects against several cardiovascular disorders. However, the extent to which the impact contribution of each cell death pathway in the pathogenesis of cardiac I/R injury is unclear. To elucidate the different significance of each cell death mode in the same cardiac I/R injury setting is beneficial to discover an ideal cardioprotective strategy against I/R injury. In the present study, we hypothesized that 1) apoptosis, necroptosis, and ferroptosis are involved in the pathogenesis of cardiac I/R injury with varying significant contributions. 2) Inhibitors of apoptosis, necroptosis, and ferroptosis provide different degrees of cardioprotection against cardiac I/R injury by reducing cardiac inflammation, mitochondrial dysfunction, and cell death. 3) Combined apoptosis and ferroptosis inhibitors reduced cardiac I/R injury better than a single regimen by attenuating inflammation, mitochondrial dysfunction, and cell death. To test the first and second hypothesis, one hundred and twenty-six male Wistar rats were subjected to sham or cardiac I/R operation. Rats in the I/R group were divided into vehicle and apoptosis inhibitor (Z-vad), necroptosis inhibitor (Nec-1), and ferroptosis inhibitor (Fer-1). Rats in each treatment group were subdivided into low, medium, and high dose regimens. All treatments were given to the rats via intravenous injection 15 min before ischemia. The left anterior descending (LAD) coronary artery was ligated to induce ischemia for 30 min, followed by 120-min reperfusion. During the I/R protocol, left ventricular (LV) function and arrhythmia parameters were measured. After I/R protocol, the rats were sacrificed and the heart was used to determine myocardial infarct size, mitochondrial function, mitochondrial dynamics, cardiac inflammation, and cell death pathway of apoptosis, necroptosis, and ferroptosis. Our results showed that cardiac I/R injury caused cardiac inflammation, mitochondrial damage, apoptosis, and ferroptosis cell death, leading to arrhythmia, myocardial infarction, and LV dysfunction. Furthermore, myocardial infarct size, LV dysfunction, and mitochondrial dysfunction were reduced after treatment with low and medium dose of Z-vad, medium and high dose of Fer-1. Fer-1 attenuated cardiac inflammation and mitochondrial dynamics imbalance. Moreover, Z-vad and Fer-1 suppressed apoptosis, while a high dose of Z-vad, and medium and high doses of Fer-1 reduced ferroptosis. Additionally, necroptosis did not occur in our cardiac I/R setting, and Nec-1 had no cardioprotective benefits in the current cardiac I/R model although it could reduce cardiac inflammation during cardiac I/R injury. All cell death inhibitor did not diminish cardiac arrhythmias. Thus, these results demonstrated that apoptosis and ferroptosis play a significant role during cardiac I/R injury in rats. To test the third hypothesis, fifty-four male Wistar rats weighing 400-500 g were received a combined apoptosis and ferroptosis inhibitor. For the combined treatment, Z- vad (medium dose) and Fer-1 (medium dose) was chosen. The treatment was given to the rats 15 min before ischemia through intravenous injection, then the rats were subjected to 30 min of cardiac ischemia and 120 min of reperfusion. Myocardial infarct size, mitochondrial function, mitochondrial dynamics, inflammation, cell death pathways were evaluated after the cardiac I/R protocol. Medium dose of Z-vad and Fer-1, and the combined treatment improved LV function and reduced infarct size, decreased mitochondrial ROS levels and mitochondrial membrane depolarization. Moreover, medium dose of Fer-1 and combined treatment attenuated mitochondrial swelling, mitochondrial dynamic imbalance, and cardiac inflammation. Apoptotic proteins and ferroptotic proteins expression levels were also reduced in all treatment groups. The combined treatment did not show a superior advantage than the single treatment. In summary apoptosis and ferroptosis are the significant modes of cell death associated with the pathogenesis of acute cardiac I/R injury. Inhibitors of apoptosis, necroptosis, and ferroptosis provide different degrees of cardioprotection against cardiac I/R injury. Inhibitors of either apoptosis or ferroptosis similarly alleviated cardiac mitochondrial dysfunction, reduced apoptosis and ferroptosis, resulting in decreased infarct size led to improved LV function in rats with cardiac I/R injury. Ferroptosis inhibitor restored the balance of mitochondrial dynamics. Necroptosis inhibitor attenuated cardiac inflammation, but not cardioprotection effect.
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