Wang Shanjie, Chen Kegong, Wang Ye, Wang Zeng, Li Zhaoying, Guo JunChen, Chen Jianfeng, Liu Wenhua, Guo Xiaohui, Yan Guangcan, Liang Chenchen, Yu Huai, Fang Shaohong, Yu Bo
The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Heilongjiang Key Laboratory for Accurate Diagnosis and Treatment of Coronary Heart Disease, Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, China.
Department of Thoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Biomater Res. 2023 May 5;27(1):41. doi: 10.1186/s40824-023-00377-8.
Large-dose melatonin treatment in animal experiments was hardly translated into humans, which may explain the dilemma that the protective effects against myocardial injury in animal have been challenged by clinical trials. Ultrasound-targeted microbubble destruction (UTMD) has been considered a promising drug and gene delivery system to the target tissue. We aim to investigate whether cardiac gene delivery of melatonin receptor mediated by UTMD technology optimizes the efficacy of clinically equivalent dose of melatonin in sepsis-induced cardiomyopathy.
Melatonin and cardiac melatonin receptors in patients and rat models with lipopolysaccharide (LPS)- or cecal ligation and puncture (CLP)-induced sepsis were assessed. Rats received UTMD-mediated cardiac delivery of RORα/cationic microbubbles (CMBs) at 1, 3 and 5 days before CLP surgery. Echocardiography, histopathology and oxylipin metabolomics were assessed at 16-20 h after inducing fatal sepsis.
We observed that patients with sepsis have lower serum melatonin than healthy controls, which was observed in the blood and hearts of Sprague-Dawley rat models with LPS- or CLP-induced sepsis. Notably, a mild dose (2.5 mg/kg) of intravenous melatonin did not substantially improve septic cardiomyopathy. We found decreased nuclear receptors RORα, not melatonin receptors MT1/2, under lethal sepsis that may weaken the potential benefits of a mild dose of melatonin treatment. In vivo, repeated UTMD-mediated cardiac delivery of RORα/CMBs exhibited favorable biosafety, efficiency and specificity, significantly strengthening the effects of a safe dose of melatonin on heart dysfunction and myocardial injury in septic rats. The cardiac delivery of RORα by UTMD technology and melatonin treatment improved mitochondrial dysfunction and oxylipin profiles, although there was no significant influence on systemic inflammation.
These findings provide new insights to explain the suboptimal effect of melatonin use in clinic and potential solutions to overcome the challenges. UTMD technology may be a promisingly interdisciplinary pattern against sepsis-induced cardiomyopathy.
动物实验中的大剂量褪黑素治疗很难应用于人类，这或许可以解释动物实验中对心肌损伤的保护作用在临床试验中受到挑战这一困境。超声靶向微泡破坏（UTMD）被认为是一种有前景的向靶组织递送药物和基因的系统。我们旨在研究UTMD技术介导的褪黑素受体心脏基因递送是否能优化临床等效剂量的褪黑素在脓毒症诱导的心肌病中的疗效。
评估脂多糖（LPS）或盲肠结扎穿孔（CLP）诱导的脓毒症患者及大鼠模型中的褪黑素和心脏褪黑素受体。大鼠在CLP手术前1、3和5天接受UTMD介导的RORα/阳离子微泡（CMB）心脏递送。在诱导致死性脓毒症后16 - 20小时评估超声心动图、组织病理学和氧化脂质代谢组学。
我们观察到脓毒症患者的血清褪黑素低于健康对照，在LPS或CLP诱导的脓毒症Sprague - Dawley大鼠模型的血液和心脏中也观察到这种情况。值得注意的是，静脉注射低剂量（2.5mg/kg）的褪黑素并不能显著改善脓毒症心肌病。我们发现在致死性脓毒症情况下，核受体RORα减少，而非褪黑素受体MT1/2减少，这可能削弱了低剂量褪黑素治疗的潜在益处。在体内，重复进行UTMD介导的RORα/CMB心脏递送表现出良好的生物安全性、效率和特异性，显著增强了安全剂量的褪黑素对脓毒症大鼠心脏功能障碍和心肌损伤的作用。UTMD技术介导的RORα心脏递送和褪黑素治疗改善了线粒体功能障碍和氧化脂质谱，尽管对全身炎症没有显著影响。
这些发现为解释临床使用褪黑素效果欠佳的原因及克服相关挑战的潜在解决方案提供了新见解。UTMD技术可能是一种有前景的跨学科治疗脓毒症诱导的心肌病的模式。
