Long noncoding RNA Crnde attenuates cardiac fibrosis via Smad3‐Crnde negative feedback in diabetic cardiomyopathy

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.

TGF-β and WNT signaling pathways in cardiac fibrosis: non-coding RNAs come into focus

“…Inhibited the binding of Smad3 to the α-SMA gene promoter via interacting with rSBEs DCM/Human, mouse/CFs Anti [199] miR-29 led to greater stability in the aortic walls, and prevented rupture by increasing the expression of several ECM genes, such as Col1A1, Col3A1, and elastin [170]. It is indicated that TGFβ could repress miR-29 expression under cardiac stress [154].…”

Long Non-Coding RNAs in Atrial Fibrillation: Pluripotent Stem Cell-Derived Cardiomyocytes as a Model System

“…Knockdown of MIAT in vivo reduced cardiac fibrosis, deregulated fibrosis genes, and restored heart function, suggesting MIAT is another potential therapeutic target to treat fibrosis. There are other examples of lncRNAs involved in cardiac fibrosis including n379519 [ 116 , 117 ], which promotes cardiac fibrosis by sponging miR-30 [ 88 ], and Crnde, which attenuates cardiac fibrosis in a negative feedback loop with Smad3 in diabetic cardiomyopathy [ 89 ].…”

Sophocarpine Suppresses NF-κB-Mediated Inflammation Both In Vitro and In Vivo and Inhibits Diabetic Cardiomyopathy

“…Cardiovascular disease is a major cause of morbidity and mortality worldwide, especially for patients with diabetes (Tall and Levine, 2017; He et al, 2019; Tall and Jelic, 2019). Previous studies have reported that more than half of these patients die from diabetic cardiomyopathy (DCM), which is characterized by changes in myocardial structure and function such as ventricular hypertrophy, cardiac fibrosis, and heart failure (Ye et al, 2018; Kang et al, 2019; Knapp et al, 2019; Zheng et al, 2019). Due to the increased prevalence of DCM-related mortality, an understanding of the mechanism of DCM pathogenesis and effective therapies are needed urgently (Sun et al, 2019; Zheng et al, 2019; Wu et al, 2019b).…”