The Function of Circular RNAs in Myocardial Ischemia-Reperfusion Injury: Underlying Mechanisms and Therapeutic Advancement.

Myocardial ischemia reperfusion injury (MIRI) represents a prevalent and severe cardiovascular condition that arises primarily after myocardial infarction recanalization, cardiopulmonary bypass surgery, and both stable and unstable angina pectoris. MIRI can induce malignant arrhythmias and heart failure, thereby increasing the morbidity and mortality rates associated with cardiovascular diseases. Hence, it is important to assess the potential pathological mechanisms of MIRI and develop effective treatments. The role of circular RNAs (circRNAs) in MIRI has increasingly become a topic of interest in recent years. Moreover, significant evidence suggests that circRNAs play a critical role in MIRI pathogenesis, thereby representing a promising therapeutic target. This review aimed to provide a comprehensive overview of the current understanding of the role of circRNAs in MIRI and discuss the mechanisms through which circRNAs contribute to MIRI development and progression, including their effects on apoptosis, inflammation, oxidative stress, and autophagy. Furthermore, the potential therapeutic applications of circRNAs in MIRI treatment, including the use of circRNA-based therapies and modulation of circRNA expression levels, have been explored. Overall, this paper highlights the importance of circRNAs in MIRI and underscores their potential as novel therapeutic targets.

PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats.

OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite technique for thoracotomy in advanced cardiovascular surgery. However, the consequent myocardial ischemia-reperfusion injury (MIRI) is the primary culprit behind cardiac dysfunction and fatal consequences post-operation. Prior research has posited that myocardial insulin resistance (IR) plays a vital role in exacerbating the progression of MIRI. Nonetheless, the exact mechanisms underlying this phenomenon remain obscure. METHODS: We constructed pyruvate dehydrogenase E1 α subunit (PDHA1) interference and overexpression rats and used ascending aorta occlusion in an in vivo model of CPB-MIRI. We devised an in vivo model of CPB-MIRI by constructing rat models with both pyruvate dehydrogenase E1α subunit (PDHA1) interference and overexpression through ascending aorta occlusion. We analyzed myocardial glucose metabolism and the degree of myocardial injury using functional monitoring, biochemical assays, and histological analysis. RESULTS: We discovered a clear downregulation of glucose transporter 4 (GLUT4) protein content expression in the CPB I/R model. In particular, cardiac-specific PDHA1 interference resulted in exacerbated cardiac dysfunction, significantly increased myocardial infarction area, more pronounced myocardial edema, and markedly increased cardiomyocyte apoptosis. Notably, the opposite effect was observed with PDHA1 overexpression, leading to a mitigated cardiac dysfunction and decreased incidence of myocardial infarction post-global ischemia. Mechanistically, PDHA1 plays a crucial role in regulating the protein content expression of GLUT4 on cardiomyocytes, thereby controlling the uptake and utilization of myocardial glucose, influencing the development of myocardial insulin resistance, and ultimately modulating MIRI. CONCLUSION: Overall, our study sheds new light on the pivotal role of PDHA1 in glucose metabolism and the development of myocardial insulin resistance. Our findings hold promising therapeutic potential for addressing the deleterious effects of MIRI in patients.

Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury.

BACKGROUND: Previous studies proved that pyrin domain-containing protein 3 (NLRP3)-induced pyroptosis plays an important role in Myocardial ischemia-reperfusion injury (MIRI). Insulin can inhibit the activation of NLRP3 inflammasome, although the exact mechanism remains unclear. The aim of this study was to determine whether insulin reduces NLRP3-induced pyroptosis by regulating pyruvate dehydrogenase E1alpha subunit (PDHA1) dephosphorylation during MIRI. METHODS: Rat hearts were subject to 30 min global ischemia followed by 60 min reperfusion, with or without 0.5 IU/L insulin. Myocardial ischemia-reperfusion injury was evaluated by measuring myocardial enzymes release, Cardiac hemodynamics, pathological changes, infarct size, and apoptosis rate. Cardiac aerobic glycolysis was evaluated by measuring ATP, lactic acid content, and pyruvate dehydrogenase complex (PDHc) activity in myocardial tissue. Recombinant adenoviral vectors for PDHA1 knockdown were constructed. Pyroptosis-related proteins were measured by Western blotting analysis, immunohistochemistry staining, and ELISA assay, respectively. RESULTS: It was found that insulin significantly reduced the area of myocardial infarction, apoptosis rate, and improved cardiac hemodynamics, pathological changes, energy metabolism. Insulin inhibits pyroptosis-induced inflammation during MIRI. Subsequently, Adeno-associated virus was used to knock down cardiac PDHA1 expression. Knockdown PDHA1 not only promoted the expression of NLRP3 but also blocked the inhibitory effect of insulin on NLRP3-mediated pyroptosis in MIRI. CONCLUSIONS: Results suggest that insulin protects against MIRI by regulating PDHA1 dephosphorylation, its mechanism is not only to improve myocardial energy metabolism but also to reduce the NLRP3-induced pyroptosis.

[Myocardial protective effect of L-carnitine in cardioplegia solution on patients undergoing heart valve replacement operation].

OBJECTIVE: To investigate the myocardial protective effect of L-carnitine as an ingredient of cardiac arresting solution in the process of heart valve replacement operation. METHODS: 69 cases undergoing heart valve replacement with cardiopulmonary bypass (CPB), 47 males and 22 females, aged 48.17 +/- 14.22 (16 approximately 74 years), were divided into 3 groups: test group I (n = 22, 12 g/L L-carnitine was put in the St. Thomas II cold crystal cardiac arresting liquid), test group II (n = 24, 6 g/L L-carnitine was put in the St. Thomas II cold crystal cardiac arresting liquid), and control group (n = 23, no L-carnitine was put in the St. Thomas II cold crystal cardiac arresting liquid). Before operation, 20 minutes after the beginning of shunt, after the finish of shunt, and 8 hours, one day, 3 days, and 7 days after operation venous blood was drawn to test the serum cardial tropnin I (cTnI), aspartate transaminase, lactate dehydrogenase, creatine kinase (CK) and CK-MB isozyme. Heart color ultrasonography was conducted to test the cardiac index (CI) and left heart ejecting fraction (EF) one day before operation and 7 days after operation. Before shunt and by the end of intracardiac procedure a bit of myocardial tissue was taken to undergo electron microscopy. The amounts of vaso-active drugs, such as dopamine and dobutamine, used postoperatively, and the postoperative cardiac auto-rebeating rate were recorded. RESULTS: The Amounts of vaso-active drugs used after operation was 329 +/- 54 mg in the test group I and 339 +/- 47 mg in the test group II, both significantly less than in the control group (669 +/- 56 mg, both P < 0.01) without a significant difference between the 2 test groups. Since the end of CPB to 3 days after operation, the serum levels of cTnI, aspartate transaminase, lactate dehydrogenase, CK and CK-MB isozyme were significantly lower in the 2 test groups than in the control group (P < 0.05 or P < 0.01). The serum level of cTnI in test group I was significantly lower than in the test group II (5.71 +/- 1.14 ng/ml vs 7.87 +/- 1.89 ng/ml 1 day postoperatively (P < 0.05), and 5.01 +/- 0.89 ng/ml vs 7.53 +/- 1.43 ng/ml 3 days postoperatively (P < 0.05). The postoperative cardiac auto-rebeating rate was 87.9% in the test group I and 74.3% in the test group II, both significantly higher than that in the control group (45.7%, P < 0.05 and P < 0.01). Heart color ultrasonogram showed that 7 days postoperatively the CI index was 2.86 +/- 0.55 and 2.74 +/- 0.56 in the 2 test groups, significantly higher than that in the control group (2.11 +/- 0.35, both P < 0.05), and the left heart EF were 64.3 +/- 8.6 and 59.1 +/- 6.7 in the 2 test groups, both significantly higher than that in the control group (51.7 +/- 4.9, both P < 0.05). Electron microscopy showed only slight swelling of mitochondria in the cardial cell and the myocardial fiber was intact by the end of operation in the 2 test groups without significant difference between these 2 groups, however, in the control group swelling of mitochondria with vesicle formation, fissure of part of mitochondrial ridges, and disappearance of glycogen particles were found. CONCLUSION: Antegrade coronary perfusion of L-carnitine has a good protective effect on myocardium and is worth spreading for heart valve replacement patients with cardiopulmonary bypass.