Noncoding RNAs are important for regulation of cardiac hypertrophy. The function of MALAT1 (a long noncoding mRNA), miR-181a, and HMGB2; their contribution to cardiac hypertrophy; and the regulatory relationship between them during this process remain unknown. In the present study, we treated primary cardiomyocytes with angiotensin II (Ang II) to mimic cardiac hypertrophy. MALAT1 expression was significantly downregulated in Ang II-treated cardiomyocytes compared with control cardiomyocytes. Ang II-induced cardiac hypertrophy was suppressed by overexpression of MALAT1 and promoted by genetic knockdown of MALAT1. A dual-luciferase reporter assay demonstrated that MALAT1 acted as a sponge for miR-181a and inhibited its expression during cardiac hypertrophy. Cardiac hypertrophy was suppressed by overexpression of a miR-181a inhibitor and enhanced by overexpression of a miR-181a mimic. HMGB2 was downregulated during cardiac hypertrophy and was identified as a target of miR-181a by bioinformatics analysis and a dual-luciferase reporter assay. miR-181a overexpression decreased the mRNA and protein levels of HMGB2. Rescue experiments indicated that MALAT1 overexpression reversed the effect of miR-181a on HMGB2 expression. In summary, the results of the present study show that MALAT1 acts as a sponge for miR-181a and thereby regulates expression of HMGB2 and development of cardiac hypertrophy. The novel MALAT1/miR-181a/HMGB2 axis might play a crucial role in cardiac hypertrophy and serve as a new therapeutic target.
IntroductionCardiac hypertrophy is an independent risk factor for heart failure. However, the underlying mechanisms of cardiac hypertrophy are still unclear. Nintedanib is a Food and Drug Administration (FDA) approved therapeutic agent for the treatment of progressive fibrosing lung diseases.Material and methodsIn this study, we examined the effects of nintedanib on cardiac hypertrophy using an in vivo murine model with the transverse aortic constriction (TAC) operation and an in vitro cardiomyocytes model stimulated with Ang II.ResultsNintedanib has a protective effect on cardiac function in TAC mice with decreased heart rates, heart weight/body weight (HW/BW), and reduced plasma levels of creatine kinase-MB (CK-MB) and aspartate aminotransferase (AST). Wheat germ agglutinin (WGA) staining proved that the increased cardiomyocytes sizes in TAC mice were restored by nintedanib treatment. Nintedanib also reversed the decreased plasma levels of oxidative markers nuclear factor erythroid-2-related factor 2 (Nrf2), lipid peroxidation products thiobarbituric acid reactive substances (TBARS), and GSH, as well the increased homocysteine (Hcy) levels in TAC mice. In the in vitro cardiomyocytes model, cells were treated with nintedanib, followed by Ang II stimulation. Nintedanib improved Ang II induction-caused cell injury and oxidative stress in H9C2 cells, as shown by the decreased release of lactate dehydrogenase (LDH), and elevated mRNA levels of GPX1 and HO-1. Mechanistically, we prove that the protective effect of nintedanib is mediated by SIRT1.ConclusionsIn conclusion, this study demonstrates the protective effects of nintedanib on cardiac hypertrophy both in vivo and in vitro, which was attributed to its anti-oxidative activity through regulating SIRT1 expression.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.