Ablation of lncRNA Miat attenuates pathological hypertrophy and heart failure

Abstract

Rationale:The conserved long non-coding RNA (lncRNA) myocardial infarction associate transcript (Miat) was identified for its multiple single-nucleotide polymorphisms that are strongly associated with susceptibility to MI, but its role in cardiovascular biology remains elusive. Here we investigated whether Miat regulates cardiac response to pathological hypertrophic stimuli. Methods: Both an angiotensin II (Ang II) infusion model and a transverse aortic constriction (TAC) model were used in adult WT and Miat-null knockout (Miat-KO) mice to induce pathological cardiac hypertrophy. Heart structure and function were evaluated by echocardiography and histological assessments. Gene expression in the heart was evaluated by RNA sequencing (RNA-seq), quantitative real-time RT-PCR (qRT-PCR), and Western blotting. Primary WT and Miat-KO mouse cardiomyocytes were isolated and used in Ca 2+ transient and contractility measurements. Results: Continuous Ang II infusion for 4 weeks induced concentric hypertrophy in WT mice, but to a lesser extent in Miat-KO mice. Surgical TAC for 6 weeks resulted in decreased systolic function and heart failure in WT mice but not in Miat-KO mice. In both models, Miat-KO mice displayed reduced heart-weight to tibia-length ratio, cardiomyocyte cross-sectional area, cardiomyocyte apoptosis, and cardiac interstitial fibrosis and a better-preserved capillary density, as compared to WT mice. In addition, Ang II treatment led to significantly reduced mRNA and protein expression of the Ca 2+ cycling genes Sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) and ryanodine receptor 2 (RyR2) and a dramatic increase in global RNA splicing events in the left ventricle (LV) of WT mice, and these changes were largely blunted in Miat-KO mice. Consistently, cardiomyocytes isolated from Miat-KO mice demonstrated more efficient Ca 2+ cycling and greater contractility. Conclusions: Ablation of Miat attenuates pathological hypertrophy and heart failure, in part, by enhancing cardiomyocyte contractility.

Aerobic Exercise Inhibited P2X7 Purinergic Receptors to Improve Cardiac Remodeling in Mice With Type 2 Diabetes

“…Given that lncRNA MIAT and miR-150 have base binding sites ( Figure 12A ), and was responsible for the cardiac hypertrophy and fibrosis ( Qu et al, 2017 ; Yang et al, 2021 ), we investigated the expression levels of LncRNA MIAT and miR-150 ( Figures 12B–G ). We found that lncRNA MIAT was significantly increased and miR-150 expression was down-regulated in cardiac tissues of diabetic mice.…”

“…Taken these data, and considering some base binding sites exists between lncRNA MIAT and miR-150, we speculated lncRNA MIRT/miR-150 may be downstream mechanism for exercise training to inhibit P2X7R improving myocardial remodeling in diabetic mice ( Figure 12 ). Additionally, Liu Yang et al showed that ablation of lncRNA MIAT attenuates pathological hypertrophy and heart failure in both angiotensin II infusion and transverse aortic constriction model ( Yang et al, 2021 ), and alleviated cardiac fibrosis. Considering the result from rats with mycardial infarction, the positive effect of exercise training in attenuating cardiac fibrosis partially mediated through reducing of lncRNA MIAT ( Farsangi et al, 2021 ), it seems that lncRNA MIAT may be a potential therapeutic target in the regulation of various cardiac remodeling.…”

Non-Coding RNAs in the Therapeutic Landscape of Pathological Cardiac Hypertrophy

“…Furthermore, miR-328, miR-25, and MIAT promote cardiac hypertrophy by downregulating SERCA2a, and thus, impairing calcium handling [ 88 , 89 ]. In vivo inhibition of these four ncRNAs resulted in attenuated hypertrophy in mice subjected to TAC, which may be, to some extent, linked to improved calcium handling and enhanced cardiomyocyte contractility [ 90 ].…”

Periplocymarin alleviates pathological cardiac hypertrophy via inhibiting the JAK2/STAT3 signalling pathway

“…2,3 Accumulated evidence indicates that pathological cardiac hypertrophy invariably induces cardiomyocyte death, interstitial fibrosis, myocardial inflammation, diastolic and systolic dysfunction, accompanied by an increased size and mass of myocardial cells and up-regulation of foetal gene (atrial natriuretic peptide [ANP], collagen I, β-myosin heavy chain [β-MHC]) expressions. [4][5][6][7] Therefore, exploring the underlying mechanism, and effective prevention and treatment measures for pathological myocardial hypertrophy, remains of considerable significance.…”

“…Physiological cardiac hypertrophy does not develop into heart failure, while pathological cardiac hypertrophy typically develops into heart failure and can even induce sudden death 2,3 . Accumulated evidence indicates that pathological cardiac hypertrophy invariably induces cardiomyocyte death, interstitial fibrosis, myocardial inflammation, diastolic and systolic dysfunction, accompanied by an increased size and mass of myocardial cells and up‐regulation of foetal gene (atrial natriuretic peptide [ANP], collagen I, β‐myosin heavy chain [β‐MHC]) expressions 4–7 …”