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.
Highlights
Myocardial infarction (MI) is the leading cause of global mortality and morbidity [51] and typically occurs because of an acute blockage in a coronary artery
The present study focused on downregulated long noncoding RNAs (lncRNAs)
We identified a total of 36 lncRNAs downregulated in both myocardial infarction (MI)-3d and MI-14d time points (Fig. 1c, d and Supplementary Table1)
Summary
Myocardial infarction (MI) is the leading cause of global mortality and morbidity [51] and typically occurs because of an acute blockage in a coronary artery. Cardiac remodeling responses to ischemia are initially functional, compensatory, and adaptive; but, when sustained, structural changes extend well beyond the region of injury, which leads to pathological hypertrophy accompanied by metabolic changes, including decreased fatty acid oxidation and increased glycolysis [19]. These effects decrease ATP synthesis, which, in turn, contributes to increased susceptibility of the injured heart to the progression toward failure [14, 19, 28, 45, 46]. This abrogates the suppressive role CDK5 has on SIRT2 catalytic activity and activates downstream signaling of the LKB1-AMPK cascades to protect the heart from adverse remodeling responses
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