Long noncoding RNA Crnde attenuates cardiac fibrosis via Smad3‐Crnde negative feedback in diabetic cardiomyopathy. (1st March 2019)

• Record Type: Journal Article
• Authors: Zheng, Dezhi; Zhang, Yong; Hu, Yonghe; Guan, Jing; Xu, Lianbin; Xiao, Wenjing; Zhong, Qinyue; Ren, Chao; Lu, Jinfeng; Liang, Jiali; Hou, Jun
• Is Part Of: FEBS journal. Volume 286:Number 9(2019)
• Page Start: 1645
• Page End: 1655
• Publication Date: 2019-03-01
• Subjects: cardiac fibrosis -- Crnde -- diabetic cardiomyopathy -- long noncoding RNA; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14780
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Diabetic cardiomyopathy (DCM)—ventricular dysfunction in the absence of underlying heart disease—is a common complication of diabetes and a leading cause of mortality associated with the disease. In DCM, cardiac fibrosis is the main cause of heart failure. Although it is well‐established that the transforming growth factor‐beta signaling pathway plays a part in inducing cardiac fibrosis in DCM, details of the molecular mechanism involved remain elusive. Therefore, it is crucial to study the gene reg;ulation of key signaling effectors in DCM‐associated cardiac fibrosis. A recently emerged hotspot in the field of gene regulation is the role of long noncoding RNAs (lncRNAs). Recent evidence indicates that lncRNAs play a critical role in cardiac fibrosis; however, in DCM, the function of these regulatory RNAs have not been studied in depth. In this study, we identified a conserved cardiac‐specific lncRNA named colorectal neoplasia differentially expressed (Crnde). By analyzing 376 human heart tissues, it was found that Crnde expression is negatively correlated with that of cardiac fibrosis marker genes. Moreover, Crnde expression was shown to be enriched in cardiac fibroblasts (CFs). Overexpression of Crnde attenuated cardiac fibrosis and enhanced cardiac function in mice with DCM. Further, in vitro experiments showed that Crnde negatively regulates the myofibroblast differentiation of CFs. The expression of Crnde was activated by SMAD family member 3 (Smad3), shedding light on the underlying molecular mechanism. Interestingly, Crnde also inhibited the transcriptional activation of Smad3 on target genes, thereby inhibiting the expression of myofibroblastic marker genes in CFs. Overall, our data provide valuable insights into the development of potential anti‐cardiac fibrosis strategies centered on lncRNAs, for the treatment of DCM. Abstract : Diabetic cardiomyopathy (DCM) is a common and serious complication of diabetes. Long non‐coding RNAs have previously been linked to cardiac fibrosis; however, the role they play in DCM‐associated cardiac fibrosis remains unclear. In this study, Jun Hou and colleagues identified a cardiac‐specific lncRNA, Crnde, whose expression negatively correlated with cardiac fibrosis markers. Overexpression of Crnde attenuated cardiac fibrosis and enhanced cardiac function in DCM mice. In vitro, Crnde negatively regulated the myofibroblast differentiation of cardiac fibroblasts. The team shed light on the molecular mechanism – involving TGF‐β/Smad3 signaling – providing an interesting new avenue for development of anti‐fibrosis strategies for DCM.