Sivakumar Bhavana, Nadeem Ahmed, Dar Mashooq Ahmad, Kurian Gino A
Vascular Biology Lab, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, Tamil Nadu, India.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Life (Basel). 2023 Nov 20;13(11):2234. doi: 10.3390/life13112234.
GSK3β is a promising target for treating various disease conditions, including myocardial ischemia-reperfusion injury (IR). This study investigated the potential of GSK3β as a novel drug for managing IR in rats exposed to PM for 1 day and up to 21 days. Female Wistar rats were exposed to PM at a concentration of 250 µg/m for 3 h daily for either a single day or 21 days. After exposure, the isolated rat hearts underwent 30 min of ischemia followed by 60 min of reperfusion. GSK3β inhibition effectively reduced IR injury in rat hearts from animals exposed to PM for 1 day but not in those exposed for 21 days. PM exposure disrupted the redox balance in mitochondria and reduced the gene expression of antioxidants (glutaredoxin and peroxiredoxin) and NRF2, which protects against oxidative stress. PM also impaired mitochondrial bioenergetics, membrane potential, and quality control, leading to mitochondrial stress. Importantly, PM increased the translocation of GSK3β into mitochondria and compromised the overall mitochondrial function, particularly in the 21-day-exposed rat myocardium. The results indicate that extended exposure to PM leads to oxidative stress that disrupts mitochondrial function and diminishes the effectiveness of GSK3β inhibitors in offering cardio-protection through mitochondria.
糖原合成酶激酶3β（GSK3β）是治疗包括心肌缺血再灌注损伤（IR）在内的各种疾病状况的一个有前景的靶点。本研究调查了GSK3β作为一种新型药物用于管理暴露于颗粒物（PM）1天至21天的大鼠IR的潜力。雌性Wistar大鼠每天以250μg/m的浓度暴露于PM 3小时，持续1天或21天。暴露后，分离的大鼠心脏经历30分钟的缺血，随后60分钟的再灌注。GSK3β抑制有效地减少了暴露于PM 1天的动物的大鼠心脏中的IR损伤，但在暴露21天的动物中则没有。PM暴露破坏了线粒体中的氧化还原平衡，并降低了抗氧化剂（谷氧还蛋白和过氧化物酶）和NRF2（可抵御氧化应激）的基因表达。PM还损害了线粒体生物能量学、膜电位和质量控制，导致线粒体应激。重要的是，PM增加了GSK3β向线粒体的转位，并损害了整体线粒体功能，特别是在暴露21天的大鼠心肌中。结果表明，长期暴露于PM会导致氧化应激，从而破坏线粒体功能，并降低GSK3β抑制剂通过线粒体提供心脏保护的有效性。
