Abstract
Myocarditis (MC) is a common, potentially life-threatening inflammatory disease of the myocardium. A growing body of evidence has shown that mitogen-activated protein kinase 14 (MAPK14) participates in the pathogenesis of MC. However, the upstream regulators of MAPK14 remain enigmatic. Circular RNAs (circRNAs) have been identified to play vital roles in the pathophysiology of cardiovascular diseases. Nevertheless, the clinical significance, biological function, and regulatory mechanisms of circRNAs in MC remain poorly understood. In this study, we determined a novel circRNA, circACSL1 (ID: hsa_circ_0071542), which was significantly upregulated in the acute phase of MC, and its dynamic change in expression was related to the progression of MC. We used lipopolysaccharide (LPS) to induce the inflammatory responses in the human cardiomyocytes (HCM) line for in vitro and in cellulo experiments. The pro-inflammatory factors (IL-1β, IL-6, and TNF-α), myocardial injury markers (cTnT, CKMB, and BNP), cell viability, and cell apoptosis were measured to evaluate the extent of myocardial inflammation and myocardial injury level. Functional experiments, including gain-of-function and loss-of-function, were then performed to investigate the pro-inflammatory roles of circACSL1. The results revealed that circACSL1 could aggravate inflammation, myocardial injury, and apoptosis in HCM. Mechanistically, circACSL1 acted as a sponge for miR-8055-binding sites to regulate the downstream target MAPK14 expression. Furthermore, overexpression of miR-8055 rescued the pro-inflammatory effects of circACSL1 on HCM, and the upregulation of MAPK14 induced by circACSL1 was attenuated by miR-8055 overexpression. Knockdown of circACSL1 or overexpression of miR-8055 reduced myocardial inflammation and myocardial injury level and these effects were rescued by overexpression of MAPK14. In summary, our study demonstrated that circACSL1 could aggravate myocardial inflammation and myocardial injury through competitive absorption of miR-8055, thereby upregulating MAPK14 expression. Moreover, circACSL1 may represent a potential novel biomarker for the precise diagnosis of MC and offer a promising therapeutic target for MC treatment.
Highlights
Myocarditis (MC) is a potentially life-threatening inflammatory disease of the myocardium with a broad spectrum of clinical manifestations[1]
CircACSL1 is upregulated in MC and implicated in the progression of MC In the previous study, we detected the expression of circACSL1 in leukocytes separated from peripheral blood samples of eight MC children and eight healthy controls, and we found that circACSL1 level was upregulated in MC cases versus control patients
The results showed that the dynamic trend of circACSL1 level was consistent with hypersensitive troponin T (Hs-TnT) and NT-pro BNP expression levels (Fig. 2D–G), indicating that circACSL1 might be a potential biomarker for the diagnosis of MC pathogenesis
Summary
Myocarditis (MC) is a potentially life-threatening inflammatory disease of the myocardium (heart muscle) with a broad spectrum of clinical manifestations[1]. Diagnosis of MC in the early stage is pretty challenging owing to its diverse clinical presentations from clinically silent to rapidly progressive heart failure, cardiogenic shock, or fatal arrhythmias[6,7], and because of infrequent use of an endomyocardial biopsy, the diagnostic gold standard for MC8. The identified etiological factors are heterogeneous in nature, including viral, bacterial, or fungal pathogen-mediated infections that spread to the heart, certain immune and autoimmune condition-associated cardiac inflammation, and secondary inflammatory responses in cardiac muscles owing to drug toxicity or other illness; the exact pathogenesis of MC remains unclear[1,10]. Elucidation of the underlying pathomechanisms of the myocardial inflammation is critical for the development of effective therapeutic strategies
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