Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, No. 193, Lianhe Road, Xigang District, Dalian 11600, China.
Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
Oxid Med Cell Longev. 2022 Feb 18;2022:5044046. doi: 10.1155/2022/5044046. eCollection 2022.
Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1 VEGFR-3) and wild-type (VEGFR-3) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.
心脏淋巴管生长（淋巴管生成）和完整性对于维持组织液平衡至关重要。抑制淋巴管生成参与缺血损伤或压力超负荷后的心肌水肿和心脏重构。然而，血管紧张素 II （Ang II）诱导的心脏重构过程中淋巴管完整性是否受到破坏仍有待研究。在这项研究中，通过 Ang II（1000ng/kg/min）在 VEGFR-3 敲低（Lyve-1 VEGFR-3）和野生型（VEGFR-3）同窝仔鼠中建立心脏重构模型。结果表明，Ang II 输注不仅在时间依赖性方式下诱导心脏淋巴管生成和 VEGF-C 和 VEGFR-3 表达上调，而且增强蛋白酶体活性、MKP5 和 VE-钙黏蛋白降解、p38 MAPK 激活和淋巴管通透性增加。此外，VEGFR-3 敲低显著抑制了小鼠的心脏淋巴管生成，导致组织水肿、肥大、纤维化超氧化物产生、炎症和心力衰竭（HF）加重。相反，给予环氧酶抑制剂（一种选择性蛋白酶体抑制剂）显著减轻 Ang II 诱导的心脏水肿、重构和功能障碍；上调 MKP5 和 VE-钙黏蛋白表达；抑制 p38 MAPK；并降低 WT 小鼠的淋巴管通透性，表明抑制蛋白酶体活性对于维持淋巴管内皮细胞（LEC）完整性是必需的。研究结果表明，心脏淋巴管生成和淋巴管屏障通透性增加都与 Ang II 诱导的适应性肥大重构和功能障碍有关。蛋白酶体介导的 LEC 连接通透性增加在心脏重构的发生中起主要作用。选择性刺激淋巴管生成或抑制蛋白酶体活性可能是治疗高血压诱导的心脏重构的潜在治疗选择。
