Ulm University Medical Center, Institute for Anesthesiological Pathophysiology and Process Engineering, Ulm, Germany.
Clinic for Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany.
Front Endocrinol (Lausanne). 2020 May 14;11:299. doi: 10.3389/fendo.2020.00299. eCollection 2020.
The pathophysiology of sepsis-induced myocardial dysfunction is not resolved to date and comprises inflammation, barrier dysfunction and oxidative stress. Disease-associated reduction of tissue cystathionine-γ-lyase (CSE) expression, an endogenous HS-producing enzyme, is associated with oxidative stress, barrier dysfunction and organ injury. CSE-mediated cardio-protection has been suggested to be related the upregulation of oxytocin receptor (OTR). CSE can also mediate glucocorticoid receptor (GR) signaling, which is important for normal heart function. A sepsis-related loss of cardiac CSE expression associated with impaired organ function has been reported previously. The aim of this current study was to investigate the role of cardiac GR and OTR after polymicrobial sepsis in a clinically relevant, resuscitated, atherosclerotic porcine model. Anesthetized and instrumented FBM (Familial Hypercholesterolemia Bretoncelles Meishan) pigs with high fat diet-induced atherosclerosis underwent poly-microbial septic shock ( = 8) or sham procedure ( = 5), and subsequently received intensive care therapy with fluid and noradrenaline administration for 24 h. Cardiac protein expression and mRNA levels were analyzed. Systemic troponin, a marker of cardiac injury, was significantly increased in septic animals in contrast to sham, whereas OTR and GR expression in septic hearts were reduced, along with a down-regulation of anti-inflammatory GR target genes and the antioxidant transcription factor NRF2. These results suggest a potential interplay between GR, CSE, and OTR in sepsis-mediated oxidative stress, inflammation and cardiac dysfunction.
目前，脓毒症引起的心功能障碍的病理生理学尚未得到解决，其包括炎症、屏障功能障碍和氧化应激。与疾病相关的组织胱硫醚-γ-裂解酶（CSE）表达减少，CSE 是一种内源性产生 HS 的酶，与氧化应激、屏障功能障碍和器官损伤有关。CSE 介导的心脏保护作用与催产素受体（OTR）的上调有关。CSE 还可以介导糖皮质激素受体（GR）信号转导，这对于正常心脏功能很重要。先前已经报道过与器官功能障碍相关的脓毒症相关心脏 CSE 表达缺失。本研究的目的是在一种临床相关的、复苏的、动脉粥样硬化的猪模型中，研究多微生物脓毒症后心脏 GR 和 OTR 的作用。用高脂肪饮食诱导动脉粥样硬化的麻醉和仪器化 FBM（家族性高胆固醇血症 Bretoncelles 梅山猪）猪接受多微生物脓毒症休克（=8）或假手术（=5），随后接受 24 小时的液体和去甲肾上腺素输注强化护理治疗。分析心脏蛋白表达和 mRNA 水平。全身肌钙蛋白是心脏损伤的标志物，在脓毒症动物中明显高于假手术组，而脓毒症心脏中的 OTR 和 GR 表达降低，抗炎 GR 靶基因和抗氧化转录因子 NRF2 的下调。这些结果表明，GR、CSE 和 OTR 之间可能存在相互作用，参与脓毒症介导的氧化应激、炎症和心功能障碍。
