Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Province Key Laboratory of Cardiac Function and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Acta Biochim Biophys Sin (Shanghai). 2023 May 25;55(5):831-841. doi: 10.3724/abbs.2023071.
Systemic and pulmonary arterial hypertension (PAH) can induce left and right ventricular hypertrophy, respectively, but common therapeutic targets for both left and right hypertrophy are limited. In this study, we attempt to explore potential common therapeutic targets and screen out potential target drugs for further study. Cardiac mRNA expression profiles in mice with transverse aortic constriction (TAC) and pulmonary arterial constriction (PAC) are obtained from online databases. After bioinformatics analyses, we generate TAC and PAC mouse models to validate the phenotypes of cardiac remodelling as well as the identified hub genes. Bioinformatics analyses show that there are 214 independent differentially expressed genes (DEGs) in GSE136308 (TAC related) and 2607 independent DEGs in GSE30922 (PAC related), while 547 shared DEGs are associated with the function of the extracellular matrix (ECM) or involved in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and ECM-receptor interactions. We identifyd , , , , , , , , and as hub genes of the shared DEGs, and most of them are associated with myocardial fibrosis. Those hub genes and phenotypes of cardiac remodelling are validated in our TAC and PAC mouse models. Furthermore, we identify dehydroisoandrosterone (DHEA), iloprost and 4,5-dianilinophthalimide (DAPH) as potential therapeutic drugs targeting both left and right ventricular hypertrophy and validate the effect of DHEA. These findings suggest that DHEA could be an effective drug for pressure overload-induced left or right ventricular hypertrophy by regulating the shared hub differentially expressed genes associated with fibrosis.
系统性和肺动脉高血压（PAH）分别可引起左、右心室肥厚，但针对左、右心室肥厚的常见治疗靶点有限。在这项研究中，我们试图探索潜在的共同治疗靶点，并筛选出潜在的靶标药物进行进一步研究。从在线数据库中获得了患有主动脉缩窄（TAC）和肺动脉缩窄（PAC）的小鼠的心脏 mRNA 表达谱。经过生物信息学分析后，我们生成了 TAC 和 PAC 小鼠模型，以验证心脏重构的表型以及鉴定的枢纽基因。生物信息学分析显示，在 GSE136308（与 TAC 相关）中存在 214 个独立的差异表达基因（DEGs），在 GSE30922（与 PAC 相关）中存在 2607 个独立的 DEGs，而 547 个共享 DEGs 与细胞外基质（ECM）的功能相关或涉及 PI3K-Akt 信号通路、细胞因子-细胞因子受体相互作用和 ECM-受体相互作用。我们鉴定出、、、、、、、、和作为共享 DEGs 的枢纽基因，其中大多数与心肌纤维化相关。这些枢纽基因和心脏重构的表型在我们的 TAC 和 PAC 小鼠模型中得到了验证。此外，我们还鉴定出脱氢异雄酮（DHEA）、前列环素和 4,5-二氨基邻苯二甲酰亚胺（DAPH）作为针对左、右心室肥厚的潜在治疗药物，并验证了 DHEA 的作用。这些发现表明，DHEA 通过调节与纤维化相关的共享枢纽差异表达基因，可能成为一种有效治疗压力超负荷引起的左或右心室肥厚的药物。
