Mokhtari Behnaz, Hamidi Masoud, Badalzadeh Reza, Mahmoodpoor Ata
Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
Mol Biol Rep. 2023 Mar;50(3):2147-2158. doi: 10.1007/s11033-022-08115-4. Epub 2022 Dec 24.
Sepsis-induced myocardial dysfunction is associated with worse clinical outcomes and high mortality, but no effective therapeutic intervention has been explored, reinforcing the urgent need to develop innovative strategies. Mitochondrial dysfunction underlies the pathogenesis of sepsis-induced myocardial dysfunction. Herein, we assessed the effect of mitochondrial transplantation on sepsis-induced myocardial dysfunction in a rat model of cecal ligation and puncture (CLP)-induced sepsis.
Male Wistar rats (n = 80, 12 weeks old, 250-300 g) were divided into groups with/without CLP-induced sepsis receiving mitochondrial transplantation in single or two repetitive injections (1 h or 1 and 7 h post-CLP, respectively). Mitochondria were isolated from donor rats and injected intravenously (400 µl of mitochondrial suspension containing 7.5 × 10 mitochondria/ml of respiration buffer) in recipient groups. Twenty-four hours post-operation, LDH and cTn-I levels, mitochondrial functional endpoints, expression of mitochondrial biogenesis (SIRT-1 and PGC-1α) and fission/fusion (Drp1/Mfn1 and Mfn2) genes, and inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels were evaluated. Survival was tested over 72 h post-operation.
Mitotherapy significantly improved 72-hours survival (P < .05) and decreased LDH and cTn-I levels (P < .01). It also restored mitochondrial function and expression of mitochondrial biogenesis and fusion genes, and decreased the expression of mitochondrial fission gene and the levels of inflammatory cytokines (P < .05 to P < .01). Mitotherapy with repetitive injections at 1 and 7 h post-CLP provided noticeable mitoprotection in comparison with the group receiving mitotherapy at single injection.
Mitotherapy improved mitochondrial function, biogenesis, and dynamic associated with SIRT-1/PGC-1α network and suppressed inflammatory response in CLP-induced sepsis model, therefore, offers a promising strategy to overcome life-threatening sepsis challenge.
脓毒症诱导的心肌功能障碍与更差的临床结局和高死亡率相关，但尚未探索出有效的治疗干预措施，这凸显了开发创新策略的迫切需求。线粒体功能障碍是脓毒症诱导的心肌功能障碍发病机制的基础。在此，我们在盲肠结扎和穿刺（CLP）诱导的脓毒症大鼠模型中评估了线粒体移植对脓毒症诱导的心肌功能障碍的影响。
将雄性Wistar大鼠（n = 80，12周龄，250 - 300 g）分为有/无CLP诱导脓毒症的组，分别接受单次或两次重复注射（分别在CLP后1小时或1小时和7小时）的线粒体移植。从供体大鼠中分离出线粒体，并向受体组静脉注射（400 μl含有7.5×10个线粒体/ml呼吸缓冲液的线粒体悬液）。术后24小时，评估乳酸脱氢酶（LDH）和心肌肌钙蛋白I（cTn-I）水平、线粒体功能终点、线粒体生物发生（SIRT-1和PGC-1α）以及分裂/融合（Drp1/Mfn1和Mfn2）基因的表达，以及炎性细胞因子（TNF-α、IL-1β和IL-6）水平。在术后72小时内测试生存率。
线粒体治疗显著提高了72小时生存率（P <.05），并降低了LDH和cTn-I水平（P <.01）。它还恢复了线粒体功能以及线粒体生物发生和融合基因的表达，并降低了线粒体分裂基因的表达和炎性细胞因子水平（P <.05至P <.01）。与单次注射接受线粒体治疗的组相比，在CLP后1小时和7小时重复注射的线粒体治疗提供了显著的线粒体保护作用。
线粒体治疗改善了与SIRT-1/PGC-1α网络相关的线粒体功能、生物发生和动态变化，并抑制了CLP诱导的脓毒症模型中的炎症反应，因此，为克服危及生命的脓毒症挑战提供了一种有前景的策略。
