Long non-coding RNA KCND1 protects hearts from hypertrophy by targeting YBX1

Abstract

Cardiac hypertrophy is a common structural remodeling in many cardiovascular diseases. Recently, long non-coding RNAs (LncRNAs) were found to be involved in the physiological and pathological processes of cardiac hypertrophy. In this study, we found that LncRNA KCND1 (LncKCND1) was downregulated in both transverse aortic constriction (TAC)-induced hypertrophic mouse hearts and Angiotensin II (Ang II)-induced neonatal mouse cardiomyocytes. Further analyses showed that the knockdown of LncKCND1 impaired cardiac mitochondrial function and led to hypertrophic changes in cardiomyocytes. In contrast, overexpression of LncKCND1 inhibited Ang II-induced cardiomyocyte hypertrophic changes. Importantly, enhanced expression of LncKCND1 protected the heart from TAC-induced pathological cardiac hypertrophy and improved heart function in TAC mice. Subsequent analyses involving mass spectrometry and RNA immunoprecipitation assays showed that LncKCND1 directly binds to YBX1. Furthermore, overexpression of LncKCND1 upregulated the expression level of YBX1, while silencing LncKCND1 had the opposite effect. Furthermore, YBX1 was downregulated during cardiac hypertrophy, whereas overexpression of YBX1 inhibited Ang II-induced cardiomyocyte hypertrophy. Moreover, silencing YBX1 reversed the effect of LncKCND1 on cardiomyocyte mitochondrial function and its protective role in cardiac hypertrophy, suggesting that YBX1 is a downstream target of LncKCND1 in regulating cardiac hypertrophy. In conclusion, our study provides mechanistic insights into the functioning of LncKCND1 and supports LncKCND1 as a potential therapeutic target for pathological cardiac hypertrophy.

YB-1 Is a Novel Target for the Inhibition of α-Adrenergic-Induced Hypertrophy

“…In addition, lncKCND1 interacts with YB-1, which enhances the expression of YB-1. Using a mouse TAC model for the induction of cardiac hypertrophy, the authors demonstrated decreased lncKCND1 expression and a downregulation of YB-1 [ 23 ]. Silencing of YB-1 reversed the protective role of lncKCND1 in cardiac hypertrophy.…”

“…In contrast to our experiments in adult cardiomyocytes, Varma et al [ 28 ] found a significant reduction in cell size under baseline conditions, as well as after stimulation with PE, in neonatal rat cardiomyocytes (NRCMs) transfected with YB-1 siRNA. On the other hand, Yang et al [ 23 ] revealed a downregulation of YB-1 in AngII-stimulated neonatal mouse cardiomyocytes, indicating that the silencing of YB-1 leads to hypertrophy. Both stimulation of cardiomyocytes by AngII and alpha-adrenergic stimulation by PE lead to pathological growth via the activation of GPCRs.…”

“…Both stimulation of cardiomyocytes by AngII and alpha-adrenergic stimulation by PE lead to pathological growth via the activation of GPCRs. Varma et al [ 28 ] and Yang et al [ 23 ] also found differences in YB-1’s effects in vivo. Both used TAC-induced hypertrophic mouse hearts.…”

“…Both used TAC-induced hypertrophic mouse hearts. Whereas Varma et al [ 28 ] showed an increase in YB-1 protein levels two days after TAC, Yang et al [ 23 ] found decreased YB-1 expression in hypertrophic heart tissues four weeks after TAC. Interestingly, YB-1 protein expression was upregulated in mice four weeks after TAC despite YB-1 knockdown in the study of Varma et al [ 28 ], and the increase in cardiomyocyte cell size induced by TAC was not reduced in mouse hearts with YB-1 knockdown.…”

Long Non-Coding RNAs (lncRNAs) in Heart Failure: A Comprehensive Review

“…Another lncRNA, known as H19, shows a high degree of conservation and serves as a critical factor in the early stages of postnatal development as well as in the pathogenesis of several disorders [ 9 , 60 , 61 ]. Similarly, the expression of LncKCND1 (potassium voltage-gated channel subfamily D member 1) is increased in models of heart failure, and it functions to suppress the enlargement of cardiomyocytes by the production of miR-675 [ 62 ]. This microRNA specifically targets CaMKIIδ (Calcium/Calmodulin-Dependent Protein Kinase II delta, an enzyme that plays an important part in a variety of physiological activities, including calcium control and the formation of memory in neurons, as well as heart muscle contraction).…”