Long Noncoding RNA–DACH1 (Dachshund Homolog 1) Regulates Cardiac Function by Inhibiting SERCA2a (Sarcoplasmic Reticulum Calcium ATPase 2a)

Abstract

Heart failure (HF) is a major cause of morbidity and mortality in patients with various cardiovascular diseases. Restoration of cardiac function is critical in improving the clinical outcomes of patients with HF. Long noncoding RNAs are widely involved in the development of multiple cardiac diseases, whereas their role in regulating cardiac function remains unclear. In this study, we found that the expression of long noncoding RNA–DACH1 (dachshund homolog 1) was upregulated in the failing hearts of mice and human. We tested the hypothesis that the intronic long noncoding RNA of DACH1 (LncDACH1) can participate in the regulation of cardiac function and HF. Transgenic overexpression of LncDACH1 in the cardiac myocytes of mice led to impaired cardiac function, reduced calcium transient and cell shortening, and decreased SERCA2a (sarcoplasmic reticulum calcium ATPase 2a) protein expression. In contrast, conditional knockout of LncDACH1 in cardiac myocytes resulted in increased calcium transient, cell shortening, SERCA2a protein expression, and improved cardiac function of transverse aortic constriction induced HF mice. The same qualitative data were obtained by overexpression or knockdown of LncDACH1 with adenovirus carrying LncDACH1 or its siRNA. Moreover, therapeutic administration of adenovirus carrying LncDACH1 siRNA to transverse aortic constriction mice abolished the development of HF. Mechanistically, LncDACH1 directly binds to SERCA2a. Overexpression of LncDACH1 augments the ubiquitination of SERCA2a. LncDACH1 upregulation impairs cardiac function by promoting ubiquitination-related degradation of SERCA2a.

GAS5 protects against osteoporosis by targeting UPF1/SMAD7 axis in osteoblast differentiation

“…Currently, the treatment of osteoporosis is currently mainly aimed at osteoclasts ( Ensrud and Crandall, 2017 ; Roux and Briot, 2018 ), and the new therapy with teriparatide has shown a more curative effect in osteoporosis ( Minisola et al, 2019 ), which suggests that treatment options directed at osteoblasts are of great significance. Adenoviruses containing lncRNAs were used to treat mice and showed a significant therapeutic effect in many diseases, including ischemic myocardial injury ( Cai et al, 2019 ) and cardiac regeneration ( Ponnusamy et al, 2019 ). To clarify the possible role of Gas5 in osteoporosis treatment, we supplemented Gas5 -overexpressing adenoviruses in an osteoporosis mouse model based on the preceding results.…”

Long noncoding RNA LINC00152 promotes glioma cell proliferation via Src-YAP signaling pathway

“…LncRNA refers to a non-coding RNA of base compositions ranging from 200 nt to 100000 nt NA, and it plays an important role in the biological processes such as cell cycle regulation, epigenetic inheritance regulation, transcription regulation and post-transcription regulation etc., and it is involved in a series of diseases in nervous system, cardiovascular system and malignant tumor etc.. [13][14][15][16] With the deepening of research, it is found that, more and more LncRNA are closely related to the generation and development of brain glioma. [17,18] LINC00152 refers to a member of LncRNA family, and it has abnormal expression at malignant tumors such as liver cancer, gastric cancer and colon cancer etc.. [19,20] The latest clinical studies have shown that, LINC00152 is associated with poor clinical prognosis of brain glioma.…”

LncRNAs in cardiac hypertrophy: From basic science to clinical application

“…36,47,59,60 Conditional knockout of Lnc-DACH or overexpression Lnc-TINCR resulted in increasing calcium transient, and improving cardiac function after transverse aortic constriction in mice. 41 Inhibition of Lnc-Chaer expression before the onset of pressure overload substantially attenuates cardiac hypertrophy on mouse model. 26…”