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Updated: Jul 18, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During
Kai-Yuan Chen1,2, Zhou Liu2, Jing Yi3
1Department of Cardiovascular Surgery, the Affiliated Hospital of Guizhou Medical University, Beijing Road, Yunyan District, Guiyang, 550001, Guizhou Province, China.
Insights
Pyruvate dehydrogenase E1α subunit (PDHA1) regulates glucose metabolism and myocardial insulin resistance, impacting ischemia-reperfusion injury. Modulating PDHA1 offers a potential therapeutic strategy for cardiac dysfunction following cardiopulmonary bypass surgery.
Area of Science:
- Cardiovascular Surgery
- Metabolic Regulation
- Myocardial Pathophysiology
Background:
- Cardiopulmonary bypass (CPB) is essential for advanced cardiovascular surgery but causes myocardial ischemia-reperfusion injury (MIRI).
- Myocardial insulin resistance (IR) is implicated in worsening MIRI, but underlying mechanisms are unclear.
Purpose of the Study:
- To elucidate the role of pyruvate dehydrogenase E1α subunit (PDHA1) in CPB-induced MIRI and myocardial glucose metabolism.
- To investigate the relationship between PDHA1, glucose transporter 4 (GLUT4), and myocardial insulin resistance.
Main Methods:
- Developed in vivo rat models of CPB-MIRI with PDHA1 interference and overexpression.
- Utilized ascending aorta occlusion for CPB simulation.
- Assessed myocardial glucose metabolism and injury via functional monitoring, biochemical assays, and histology.
Main Results:
- CPB-induced MIRI models showed reduced glucose transporter 4 (GLUT4) expression.
- PDHA1 interference worsened cardiac dysfunction and myocardial injury.
- PDHA1 overexpression mitigated cardiac dysfunction and infarct size.
- PDHA1 regulates GLUT4 expression, affecting glucose uptake and MIRI.
Conclusions:
- PDHA1 is crucial for regulating myocardial glucose metabolism and insulin resistance.
- PDHA1 modulation presents a potential therapeutic target for mitigating MIRI.
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.
