Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA.
Int J Mol Sci. 2020 Nov 12;21(22):8507. doi: 10.3390/ijms21228507.
Fibroblasts are an important resident cell population in the heart involved in maintaining homeostasis and structure during normal conditions. They are also crucial in disease states for sensing signals and initiating the appropriate repair responses to maintain the structural integrity of the heart. This sentinel role of cardiac fibroblasts occurs, in part, through their ability to secrete cytokines. β-adrenergic receptors (βAR) are also critical regulators of cardiac function in the normal and diseased state and a major therapeutic target clinically. βAR are known to influence cytokine secretion in various cell types and they have been shown to be involved in cytokine production in the heart, but their role in regulating cytokine production in cardiac fibroblasts is not well understood. Thus, we hypothesized that βAR activation on cardiac fibroblasts modulates cytokine production to influence fibroblast function. Using primary fibroblast cultures from neonatal rats and adult mice, increased interleukin (IL)-6 expression and secretion occurred following β2AR activation. The use of pharmacological inhibitors and genetic manipulations showed that IL-6 elevations occurred through the Gαs-mediated activation of ERK1/2 and resulted in increased fibroblast proliferation. In vivo, a lack of β2AR resulted in increased infarct size following myocardial infarction and impaired wound closure in a murine dermal wound healing assay. These findings identify an important role for β2AR in regulating fibroblast proliferation through Gαs/ERK1/2-dependent alterations in IL-6 and may lead to the development of improved heart failure therapies through targeting fibrotic function of β2AR.
成纤维细胞是心脏中一种重要的固有细胞群体，在正常情况下参与维持心脏的内稳态和结构。在疾病状态下，它们对于感知信号和启动适当的修复反应以维持心脏的结构完整性也至关重要。心脏成纤维细胞的这种哨兵作用部分是通过其分泌细胞因子的能力实现的。β-肾上腺素能受体（βAR）也是心脏在正常和疾病状态下功能的关键调节因子，也是临床上的主要治疗靶点。βAR 已知会影响各种细胞类型的细胞因子分泌，并且已经表明它们参与心脏中的细胞因子产生，但它们在调节心脏成纤维细胞中细胞因子产生中的作用尚不清楚。因此，我们假设心脏成纤维细胞上的βAR 激活会调节细胞因子产生，从而影响成纤维细胞功能。使用来自新生大鼠和成年小鼠的原代成纤维细胞培养物，β2AR 激活后白细胞介素 (IL)-6 的表达和分泌增加。使用药理学抑制剂和基因操作表明，IL-6 升高是通过 Gαs 介导的 ERK1/2 激活引起的，导致成纤维细胞增殖增加。在体内，β2AR 缺乏会导致心肌梗死后梗死面积增加，并在小鼠皮肤伤口愈合测定中损害伤口闭合。这些发现表明β2AR 在通过 Gαs/ERK1/2 依赖性改变 IL-6 来调节成纤维细胞增殖方面发挥着重要作用，并且通过靶向β2AR 的纤维化功能，可能会导致改善心力衰竭治疗方法的发展。
