Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension.
Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension.
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DOI：
10.1161/jaha.122.027621
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发表时间：
2023-03-21
影响因子：
5.4
通讯作者：
Johns, Roger A.
中科院分区：
文献类型：
--
作者：
Lin, Qing;Kumar, Santosh;Kariyawasam, Udeshika;Yang, Xiaomei;Yang, Wei;Skinner, John T.;Gao, Wei Dong;Johns, Roger A.
心力衰竭是大多数肺动脉高压(PH)患者的主要死亡原因。作为多效性细胞因子，人抵抗素及其啮齿动物同系物--抵抗素样分子α在肺血管重塑中起着重要的力学作用。然而，目前尚不清楚这些抵抗素样分子的激活是否会直接导致PH相关的心功能障碍和重塑。在本研究中，我们检测了PH患者右室组织中的抵抗素蛋白，以及右室肥大和衰竭的啮齿动物右室组织中抵抗素样分子的表达。在人源化的小鼠模型中，心脏特异的抵抗素过度表达足以导致心脏功能障碍和重塑。扩张的心脏显示力量发育减少，细胞内钙瞬变减少。在高表达的RV组织中，收缩功能受损与抑制蛋白激酶A和AMP激活的蛋白激酶有关。从机制上讲，在转基因小鼠的右室组织中，通过高迁移率族蛋白1的信号转导，热抵抗素的激活触发了炎症反应，进而诱导了RV组织中促增殖的Ki67。有趣的是，在啮齿动物的PH模型中，我们产生的一种抗Hsisitin人类抗体可以保护心肌免受肥大和衰竭的影响。我们的研究结果表明，在心脏组织中表达了激素抵抗素，并通过其免疫调节活性在右室功能障碍和适应性不良重塑的发生发展中发挥作用。以此信号为靶点来调节心脏炎症可能为治疗人类PH相关的RV肥大和衰竭提供了一种有前途的策略。
Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin‐like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin‐like molecules can directly cause PH‐associated cardiac dysfunction and remodeling. In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin‐like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac‐specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca2+ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP‐activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage‐associated molecular pattern molecule high‐mobility group box 1, and subsequently induced pro‐proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti‐Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH‐associated RV hypertrophy and failure in humans.