LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway

Abstract

Metabolic modulation is a promising therapeutic approach to prevent adverse remodeling of the ischemic heart. Because little is known about the involvement of long non-coding RNAs (lncRNAs) in regulating cardiac metabolism, we used unbiased transcriptome profiling in a mouse model of myocardial infarction (MI). We identified a novel cardiomyocyte-enriched lncRNA, called LncHrt, which regulates metabolism and the pathophysiological processes that lead to heart failure. AAV-based LncHrt overexpression protects the heart from MI as demonstrated by improved contractile function, preserved metabolic homeostasis, and attenuated maladaptive remodeling responses. RNA-pull down followed by mass spectrometry and RNA immunoprecipitation (RIP) identified SIRT2 as a LncHrt-interacting protein involved in cardiac metabolic regulation. Mechanistically, we established that LncHrt interacts with SIRT2 to preserve SIRT2 deacetylase activity by interfering with the CDK5 and SIRT2 interaction. This increases downstream LKB1-AMPK kinase signaling, which ameliorates functional and metabolic deficits. Importantly, we found the expression of the human homolog of mouse LncHrt was decreased in patients with dilated cardiomyopathy. Together, these studies identify LncHrt as a cardiac metabolic regulator that plays an essential role in preserving heart function by regulating downstream metabolic signaling pathways. Consequently, LncHrt is a potentially novel RNA-based therapeutic target for ischemic heart disease.

LKB1 Regulates Vascular Macrophage Functions in Atherosclerosis

“…Moreover, LKB1 may participate in the regulation of ER stress and autophagy of macrophages through other pathways ( Khayati et al, 2020 ; Zuo et al, 2020 ). With the deepening of understanding, the pathophysiological value of LKB1 in cardiovascular and metabolic diseases has attracted much attention ( Liang et al, 2021 ; Liu et al, 2021 ). It has been observed that LKB1 expression is down-regulated in atherosclerotic macrophages and is involved in the regulation of atherosclerosis ( Liu et al, 2017 ).…”

Long non-coding RNAs in the pathogenesis of heart failure: A literature review

“…lncRNA cardiomyocyte-enriched non-coding transcript (Caren) preserves cardiac function during pressure overload by suppressing the ataxia telangiectasia mutated (ATM)/DNA damage response (DDR) pathway, thus maintaining mitochondrial biogenesis and function ( 35 ). LncHrt modulates the deacetylase activity of sirtuin 2, which enhances the oxidative phosphorylation (OXPHOS) capacity of mitochondria, thereby preserving cardiac metabolic homeostasis and function ( 36 ).…”

“…It has been well established that lncRNAs play an important role in myocardial infarction (MI)-induced cardiac fibrosis and HF, such as lncRNA-Safe ( 74 ), LncHrt ( 36 ), Wisp2 super-enhancer-associated RNA (Wisper) ( 75 ), and cardiac fibroblast-associated transcript (Cfast) ( 76 ). All of them are enriched in fibroblasts.…”

The Emerging Role of Non-Coding RNAs in Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells

“…LncRNAs are now known to exert influence on diverse biological processes, such as cell cycle ( Guiducci and Stojic, 2021 ), proliferation ( Liu et al, 2021 ), metastasis ( Hong et al, 2021 ), and differentiation ( Li. et al, 2021 ), as well as several diseases ( Li et al, 2021 ; Liu et al, 2021 ; Xin and Liu, 2021 ). Moreover, emerging evidence shows that lncRNAs participate in the osteogenic differentiation of BMSCs.…”