Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China.
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
Acta Pharmacol Sin. 2024 Mar;45(3):531-544. doi: 10.1038/s41401-023-01179-3. Epub 2023 Nov 2.
Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating β-adrenergic receptors (β-AR). Recent evidence shows that myeloid differentiation factor 2 (MD2), a key protein in endotoxin-induced inflammation, mediates inflammatory heart diseases. In this study, we investigated the role of MD2 in ISO-β-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg·kg·d) via osmotic mini-pumps for 2 weeks. We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice. Either MD2 knockout or administration of MD2 inhibitor L6H21 (10 mg/kg every 2 days, i.g.) could prevent mouse hearts from ISO-induced inflammation, remodelling and dysfunction. Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries. In ISO-treated H9c2 cardiomyocyte-like cells, neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages, MD2 knockout or pre-treatment with L6H21 (10 μM) alleviated ISO-induced inflammatory responses, and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts. We demonstrated that ISO induced MD2 activation in cardiomyocytes via β1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via β2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.
心肌炎症通过激活β肾上腺素能受体（β-AR）导致异丙肾上腺素（ISO）诱导的心力衰竭（HF）。最近的证据表明，髓样分化因子 2（MD2），一种内毒素诱导炎症的关键蛋白，介导炎症性心脏病。在这项研究中，我们研究了 MD2 在 ISO-β-AR 诱导的心脏损伤和 HF 中的作用。通过渗透微型泵向小鼠输注 ISO（30mg·kg·d）持续 2 周。我们发现 ISO 刺激的小鼠心脏组织中，心肌细胞和心脏巨噬细胞中的 MD2 显著增加和激活。MD2 敲除或给予 MD2 抑制剂 L6H21（10mg/kg，每 2 天一次，口服）均可防止 ISO 诱导的小鼠心脏炎症、重构和功能障碍。骨髓移植研究表明，心肌细胞 MD2 和骨髓来源的巨噬细胞 MD2 均有助于 ISO 诱导的心脏炎症和损伤。在 ISO 处理的 H9c2 心肌样细胞、新生大鼠原代心肌细胞和原代小鼠腹腔巨噬细胞中，MD2 敲除或用 L6H21（10μM）预处理可减轻 ISO 诱导的炎症反应，来自 ISO 刺激的巨噬细胞的条件培养基促进心肌细胞和成纤维细胞的肥大和纤维化。我们证明 ISO 通过β1-AR-cAMP-PKA-ROS 信号轴在心肌细胞中诱导 MD2 激活，并通过β2-AR-cAMP-PKA-ROS 轴在巨噬细胞中诱导炎症反应。这项研究确定 MD2 是 ISO 诱导的心力衰竭的关键炎症介质和有前途的治疗靶点。
