Downregulation of lncRNA MALAT1 Inhibits Angiotensin II-induced Hypertrophic Effects of Cardiomyocytes by Regulating SIRT4 via miR-93-5p.

Abstract

Cardiac hypertrophy is a leading risk for heart failure and sudden death. Long non-coding RNAs (lncRNAs) have been implicated in a variety of human diseases, including cardiac hypertrophy. We aimed to investigate the potential role and functional mechanism of lncRNA metastasis-associated in lung adenocarcinoma transcript 1 (MALAT1) in cardiac hypertrophy. C57BL/6 mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy in vivo. The expression of MALAT1, miR-93-5p, and sirtuin 4 (SIRT4) mRNA was detected using a quantitative real-time polymerase chain reaction. The protein levels of cardiac hypertrophy-related markers, including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC), and SIRT4 were measured via western blotting. The putative interaction between miR-93-5p and MALAT1 or SIRT4 was verified using a dual-luciferase reporter assay, RNA immunoprecipitation assay, or pull-down assay. Consequently, the expression of MALAT1 and SIRT4 was increased in TAC-treated mouse heart and angiotensin II (Ang-II)-induced cardiomyocytes, whereas the expression of miR-93-5p was decreased. Ang-II promoted the expression of ANP, BNP, and β-MHC and the surface area of cardiomyocytes, whereas MALAT1 downregulation impaired their expression and cell area. MiR-93-5p was a target of MALAT1, and its inhibition reversed the effects of MALAT1 downregulation. More importantly, MALAT1 modulated SIRT4 expression by degrading miR-93-5p. The expression of ANP, BNP, and β-MHC suppressed by miR-93-5p restoration was recovered by SIRT4 promotion. Overall, MALAT1 knockdown ameliorated cardiac hypertrophy partly by regulating the miR-93-5p/SIRT4 network, indicating that MALAT1 was a substantial indicator of cardiac hypertrophy.

• Authors: Huanchun Ji, Jingxian Qu, Wei Peng, Long Yang
• Journal: International heart journal (Int Heart J) Vol. 63 Issue 3 Pg. 602-611 ( 2022) ISSN: 1349-3299 [Electronic] Japan
• PMID: 35650160 (Publication Type: Journal Article)

Chemical References

• Malat1 long non-coding RNA, mouse
• MicroRNAs
• Mirn93 microRNA, mouse
• Mitochondrial Proteins
• RNA, Long Noncoding
• Angiotensin II
• Atrial Natriuretic Factor
• SIRT4 protein, mouse
• Sirtuins

Topics

• Angiotensin II (pharmacology)
• Animals
• Atrial Natriuretic Factor (metabolism)
• Cardiomegaly (metabolism)
• Down-Regulation
• Mice
• Mice, Inbred C57BL
• MicroRNAs (genetics, metabolism)
• Mitochondrial Proteins (metabolism)
• Myocytes, Cardiac (metabolism)
• Neoplasms (pathology)
• RNA, Long Noncoding (genetics, metabolism)
• Sirtuins (genetics, metabolism)