Bugga Paramesha, Stoner Michael W, Manning Janet R, Mushala Bellina A S, Bhattarai Nisha, Sharifi-Sanjani Maryam, Scott Iain
Vascular Medicine Institute University of Pittsburgh Pittsburgh Pennsylvania USA.
Center for Metabolism and Mitochondrial Medicine University of Pittsburgh Pittsburgh Pennsylvania USA.
FASEB Bioadv. 2025 Sep 12;7(9):e70049. doi: 10.1096/fba.2025-00187. eCollection 2025 Sep.
Myocardial infarction remains one of the leading causes of mortality. Reperfusion of the infarcted myocardium restores blood flow and reduces primary ischemic injury. However, despite its protective function, reperfusion is also associated with several deleterious outcomes that can result in ischemia-reperfusion (I/R) injury to cardiac tissue. Although negative outcomes such as reactive oxygen species generation are strongly associated with I/R injury, cardiac energy metabolism is also greatly disrupted. Furthermore, previous studies have shown that the restoration of normal fuel oxidation in the myocardium regulates the extent of contractile recovery. A better understanding of the pathophysiological mechanisms underlying I/R injury may allow us to develop new treatments that limit the negative aspects of the process. In this study, we examined the role played by GCN5L1, a protein implicated in the regulation of energy metabolism, in I/R injury. We demonstrate that cardiac-specific loss of GCN5L1 promotes the inhibitory phosphorylation of pyruvate dehydrogenase in vitro and in vivo, a process likely to inhibit glucose oxidation, and that this corresponds to increased myocardial damage following ischemia-reperfusion (I/R) injury.
心肌梗死仍然是主要的死亡原因之一。梗死心肌的再灌注可恢复血流并减少原发性缺血性损伤。然而，尽管再灌注具有保护作用，但它也与多种有害后果相关，这些后果可导致心脏组织的缺血再灌注（I/R）损伤。虽然诸如活性氧生成等负面结果与I/R损伤密切相关，但心脏能量代谢也会受到极大干扰。此外，先前的研究表明，心肌中正常燃料氧化的恢复调节收缩恢复的程度。更好地理解I/R损伤背后的病理生理机制可能使我们能够开发出新的治疗方法，以限制该过程的负面影响。在本研究中，我们研究了参与能量代谢调节的蛋白质GCN5L1在I/R损伤中所起的作用。我们证明，GCN5L1的心脏特异性缺失在体外和体内均促进丙酮酸脱氢酶的抑制性磷酸化，这一过程可能抑制葡萄糖氧化，并且这与缺血再灌注（I/R）损伤后心肌损伤增加相对应。
