Naghibosadat Maedeh, McClennan Andrew, Egiian Margarita, Flynn-Rizk Reema, Lalonde Tyler, Charron Carlie, Chhabra Anish, Luyt Leonard G, Dhanvantari Savita, Hoffman Lisa M
Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON N6A 3K7, Canada.
Imaging Program, Lawson Research Institute/SJHC, London, ON N6C 2R5, Canada.
Cells. 2025 Jul 1;14(13):1002. doi: 10.3390/cells14131002.
Dilated cardiomyopathy affects greater than 1 in 2500 patients worldwide, including those with the neuromuscular disorder Duchenne muscular dystrophy (DMD). While inflammation within skeletal muscle is strongly associated with DMD pathology, the key biomarkers for inflammation and possible targets for therapy within cardiac tissue in DMD-associated dilated cardiomyopathy remain to be identified. One such potential target is the myocardial ghrelin-growth hormone secretagogue receptor (GHSR) system, which is associated with cardiomyocyte survival and inhibition of inflammation. We sought to determine alterations in myocardial GHSR together with markers of cardiac inflammation using mice as a model for DMD-associated dilated cardiomyopathy. With traditional histopathology, we determined that the pathology of DMD in mice was characterized by disruption of myofiber organization, lymphocytic infiltration, and extensive cardiomyocyte vacuolization and necrosis surrounding areas of fibrosis in the left ventricular wall and apex. Using a fluorescent ghrelin analog, Cy5-ghrelin (1-19), to visualize GHSR with fluorescence confocal microscopy, we demonstrate that GHSR is elevated in myocardial tissues and correlates strongly with both F4-80 (activated macrophages) and IL-6 (pro-inflammatory cytokine), and negatively with cardiac function. We also show that GHSR can be visualized in pro-inflammatory macrophages, suggesting a direct role for GHSR in the inflammatory progression of DMD.
扩张型心肌病在全球范围内影响着超过2500分之一的患者，包括患有神经肌肉疾病杜氏肌营养不良症（DMD）的患者。虽然骨骼肌内的炎症与DMD病理密切相关，但DMD相关扩张型心肌病心脏组织中炎症的关键生物标志物和可能的治疗靶点仍有待确定。一个这样的潜在靶点是心肌胃饥饿素-生长激素促分泌素受体（GHSR）系统，它与心肌细胞存活和炎症抑制有关。我们试图以小鼠作为DMD相关扩张型心肌病的模型，确定心肌GHSR的改变以及心脏炎症标志物。通过传统组织病理学方法，我们确定小鼠DMD的病理特征为肌纤维组织破坏、淋巴细胞浸润，以及左心室壁和心尖纤维化区域周围广泛的心肌细胞空泡化和坏死。使用荧光胃饥饿素类似物Cy5-胃饥饿素（1-19），通过荧光共聚焦显微镜观察GHSR，我们证明GHSR在小鼠心肌组织中升高，并且与F4-80（活化巨噬细胞）和IL-6（促炎细胞因子）都密切相关，与心脏功能呈负相关。我们还表明GHSR可以在促炎巨噬细胞中观察到，这表明GHSR在DMD的炎症进展中起直接作用。
