Zhang Zheng, Zhang Yufang, Zou Xiaofang, Li Jiake, Chi Yunfei, Bai Hailiang, Wei Bin, Yun Huiting, Zhang Quanxi, Cao Weihua, Liu Haiyan, Duan Hongjie
Department of Diagnosis and Treatment for Cadre, Fourth Medical Center, Chinese PLA General Hospital, Beijing, China.
2 Graduate School, Hebei North University, Zhangjiakou, China.
Front Pharmacol. 2025 Apr 28;16:1560608. doi: 10.3389/fphar.2025.1560608. eCollection 2025.
Hemorrhagic shock (HS) is a critical clinical condition in which cardiac dysfunction and failure are leading causes of mortality. Mitochondrial dysfunction is central to the pathogenesis of cardiac dysfunction in HS. Irisin has been shown to improve mitochondrial function and protect against ischemia-reperfusion injury (IRI), but its specific effects on myocardial injury in HS are unknown. This study investigates irisin's therapeutic potential in a rat model of HS.
For studies, a rat HS model was established via controlled blood withdrawal and Animals were allocated to four groups: Sham, HS, HS + Vehicle (HS + Veh), and HS + Irisin. Physiological responses were evaluated through temporal sampling at 1, 3, and 6 h post-HS. For studies, H9c2 cardiomyocytes were exposed to oxygen-glucose deprivation to establish a hypoxic model. Cells were categorized into six groups: normoxia (N), normoxia + AMPK inhibitor compound C (N + Cc), hypoxia (H), hypoxia + Cc (H + Cc), hypoxia + irisin (H + Irisin), and hypoxia + Cc + irisin (H + Cc + Irisin). Cellular functional outcomes were analyzed following 3-h hypoxia exposure.
HS significantly reduced serum irisin levels. Exogenous irisin administration enhanced survival rates, stabilized mean arterial pressure (MAP), lowered lactate (LAC) levels, improved cardiac structure and function, and reduced myocardial injury biomarkers in HS rats. Mechanistically, irisin activated AMP-activated protein kinase (AMPK) and Sirtuin 1(SIRT1), to suppress the expression of dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), while upregulating mitofusin 1 (Mfn1). This modulation of mitochondrial dynamics preserved cardiomyocyte mitochondrial membrane potential (MMP), ATP production, and structural integrity. Hypoxic H9c2 cardiomyocytes exhibited consistent results. To confirm AMPK/Drp1-dependent mechanisms, Cc was administered to inhibit irisin-induced AMPK activation. Cc abolished irisin's suppression of Drp1/Fis1 and its Mfn1 upregulation. Furthermore, Cc eliminated irisin-mediated protection in both H9c2 cardiomyocytes and mitochondria.
Our study demonstrates that irisin ameliorates cardiac function and enhances early prognosis in HS. These cardioprotective effects are achieved through attenuation of myocardial damage and SIRT1/AMPK/Drp1 pathway-dependent restoration of mitochondrial homeostasis.
失血性休克（HS）是一种危急的临床病症，其中心脏功能障碍和衰竭是主要死亡原因。线粒体功能障碍是HS中心脏功能障碍发病机制的核心。已有研究表明鸢尾素可改善线粒体功能并预防缺血再灌注损伤（IRI），但其对HS心肌损伤的具体影响尚不清楚。本研究在大鼠HS模型中探究鸢尾素的治疗潜力。
在研究中，通过控制性放血建立大鼠HS模型，并将动物分为四组：假手术组、HS组、HS + 赋形剂组（HS + Veh）和HS + 鸢尾素组。在HS后1、3和6小时通过定时采样评估生理反应。在研究中，将H9c2心肌细胞暴露于氧糖剥夺以建立缺氧模型。细胞分为六组：常氧组（N）、常氧 + AMPK抑制剂化合物C组（N + Cc）、缺氧组（H）、缺氧 + Cc组（H + Cc）、缺氧 + 鸢尾素组（H + Irisin）和缺氧 + Cc + 鸢尾素组（H + Cc + Irisin）。在缺氧暴露3小时后分析细胞功能结果。
HS显著降低血清鸢尾素水平。给予外源性鸢尾素可提高HS大鼠的存活率，稳定平均动脉压（MAP），降低乳酸（LAC）水平，改善心脏结构和功能，并降低心肌损伤生物标志物水平。机制上，鸢尾素激活AMP活化蛋白激酶（AMPK）和沉默调节蛋白1（SIRT1），抑制动力相关蛋白1（Drp1）和裂变蛋白1（Fis1）的表达，同时上调线粒体融合蛋白1（Mfn1）。这种线粒体动力学调节维持了心肌细胞线粒体膜电位（MMP）、ATP生成和结构完整性。缺氧的H9c2心肌细胞表现出一致的结果。为了证实AMPK/Drp1依赖性机制，给予Cc以抑制鸢尾素诱导的AMPK活化。Cc消除了鸢尾素对Drp1/Fis1的抑制及其对Mfn1的上调作用。此外，Cc消除了鸢尾素在H9c2心肌细胞和线粒体中的保护作用。
我们的研究表明，鸢尾素可改善HS中的心脏功能并提高早期预后。这些心脏保护作用是通过减轻心肌损伤和依赖SIRT1/AMPK/Drp1途径恢复线粒体稳态来实现的。
