LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway.
Ning LiuMasaharu KataokaYingchao WangLinbin PuXiaoxuan DongXuyang FuFeng ZhangFeng GaoTian LiangJianqiu PeiChangchen XiaoQiongzi QiuTingting HongQiming ChenJing ZhaoLianlian ZhuJunhua HeXiaoyun HuYu NieWei ZhuHong YuDouglas B CowanXinyang HuJian'an WangDa-Zhi WangJinghai ChenPublished in: Basic research in cardiology (2021)
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.
Keyphrases
- heart failure
- signaling pathway
- left ventricular
- long non coding rna
- mouse model
- oxidative stress
- mass spectrometry
- poor prognosis
- skeletal muscle
- endothelial cells
- epithelial mesenchymal transition
- binding protein
- protein kinase
- traumatic brain injury
- gene expression
- small molecule
- single cell
- ms ms
- dna methylation
- transcription factor
- brain injury
- rna seq
- tyrosine kinase
- simultaneous determination
- cerebral ischemia
- nucleic acid