Department of Pharmacology, the Municipal & Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, National Medical Products Administration & State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
Department of Pharmacology, the Municipal & Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, National Medical Products Administration & State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, PR China.
Biomed Pharmacother. 2023 Sep;165:115117. doi: 10.1016/j.biopha.2023.115117. Epub 2023 Jul 3.
An increasing body of research suggests cancer-induced cardiovascular diseases, leading to the appearance of an interdisciplinary study known as onco-cardiology. Lung cancer has the highest incidence and mortality. Cardiac dysfunction constitutes a major cause of death in lung cancer patients. However, its mechanism has not been elucidated because suitable animal models that adequately mimic clinical features are lacking. Here, we established a novel chemically induced lung cancer mouse model using benzo[a]pyrene and urethane to recapitulate the general characteristics of cardiac dysfunction caused by lung cancer, the cardiac disorders in the context of the progression of lung cancer were evaluated using echocardiographic and histological approaches. The pathological changes included myocardial ischaemia, pericarditis, cardiac pre-cachexia, and pulmonary artery hypertension. We performed sequencing to detect the tRNA-derived fragments and tRNA-derived stress-induced RNAs (tRFs/tiRNAs) expressions in mouse heart tissue. 22 upregulated and 16 downregulated tRFs/tiRNAs were identified. Subsequently, the top 10 significant results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were presented. The in vitro model was established by exposing neonatal rat cardiomyocytes and myocardial fibroblasts to lung tumour cell-conditioned medium, respectively. Western blotting revealed significant changes in cardiac failure markers (atrial natriuretic peptide and α-myosin heavy chain) and cardiac fibrosis markers (Collagen-1 and Collagen-3). Our model adequately reflects the pathological features of lung cancer-induced cardiac dysfunction. Furthermore, the altered tRF/tiRNA profiles showed great promise as novel targets for therapies. These results might pave the way for research on therapeutic targets in onco-cardiology.
越来越多的研究表明，癌症会导致心血管疾病，从而出现了一门名为肿瘤心脏病学的交叉学科。肺癌的发病率和死亡率最高。心脏功能障碍是肺癌患者死亡的主要原因。然而，其机制尚未阐明，因为缺乏能够充分模拟临床特征的合适动物模型。在这里，我们使用苯并[a]芘和尿烷建立了一种新的化学诱导肺癌小鼠模型，以重现肺癌引起的心脏功能障碍的一般特征，使用超声心动图和组织学方法评估肺癌进展过程中心脏疾病。病理变化包括心肌缺血、心包炎、心脏恶病质和肺动脉高压。我们进行了测序，以检测小鼠心脏组织中的 tRNA 衍生片段和 tRNA 衍生应激诱导 RNA（tRF/tiRNA）的表达。鉴定出 22 个上调和 16 个下调的 tRF/tiRNA。随后，呈现了京都基因与基因组百科全书（KEGG）通路分析的前 10 个显著结果。通过分别将新生大鼠心肌细胞和心肌成纤维细胞暴露于肺癌肿瘤细胞条件培养基中，建立了体外模型。Western blot 显示心力衰竭标志物（心房利钠肽和α-肌球蛋白重链）和心脏纤维化标志物（胶原-1 和胶原-3）发生了显著变化。我们的模型充分反映了肺癌引起的心脏功能障碍的病理特征。此外，改变的 tRF/tiRNA 谱显示出作为治疗靶点的巨大潜力。这些结果可能为肿瘤心脏病学的治疗靶点研究铺平道路。
