TNFSF14/LIGHT promotes cardiac fibrosis and atrial fibrillation vulnerability via PI3Kγ/SGK1 pathway-dependent M2 macrophage polarisation.

BACKGROUND: Tumour necrosis factor superfamily protein 14 (TNFSF14), also called LIGHT, is an important regulator of immunological and fibrosis diseases. However, its specific involvement in cardiac fibrosis and atrial fibrillation (AF) has not been fully elucidated. The objective of this study is to examine the influence of LIGHT on the development of myocardial fibrosis and AF. METHODS: PCR arrays of peripheral blood mononuclear cells (PBMCs) from patients with AF and sinus rhythm was used to identify the dominant differentially expressed genes, followed by ELISA to evaluate its serum protein levels. Morphological, functional, and electrophysiological changes in the heart were detected in vivo after the tail intravenous injection of recombinant LIGHT (rLIGHT) in mice for 4 weeks. rLIGHT was used to stimulate bone marrow-derived macrophages (BMDMs) to prepare a macrophage-conditioned medium (MCM) in vitro. Then, the MCM was used to culture mouse cardiac fibroblasts (CFs). The expression of relevant proteins and genes was determined using qRT-PCR, western blotting, and immunostaining. RESULTS: The mRNA levels of LIGHT and TNFRSF14 were higher in the PBMCs of patients with AF than in those of the healthy controls. Additionally, the serum protein levels of LIGHT were higher in patients with AF than those in the healthy controls and were correlated with left atrial reverse remodelling. Furthermore, we demonstrated that rLIGHT injection promoted macrophage infiltration and M2 polarisation in the heart, in addition to promoting atrial fibrosis and AF inducibility in vivo, as detected with MASSON staining and atrial burst pacing respectively. RNA sequencing of heart samples revealed that the PI3Kγ/SGK1 pathway may participate in these pathological processes. Therefore, we confirmed the hypothesis that rLIGHT promotes BMDM M2 polarisation and TGB-ß1 secretion, and that this process can be inhibited by PI3Kγ and SGK1 inhibitors in vitro. Meanwhile, increased collagen synthesis and myofibroblast transition were observed in LIGHT-stimulated MCM-cultured CFs and were ameliorated in the groups treated with PI3Kγ and SGK1 inhibitors. CONCLUSION: LIGHT protein levels in peripheral blood can be used as a prognostic marker for AF and to evaluate its severity. LIGHT promotes cardiac fibrosis and AF inducibility by promoting macrophage M2 polarisation, wherein PI3Kγ and SGK1 activation is indispensable.

A Microenvironment-responsive small-molecule probe and application in quick acute myocardial infarction imaging.

Acute myocardial infarction (AMI) patients are at an elevated risk for life-threatening myocardial ischemia/reperfusion injury. Early-stage nonradioactive and noninvasive diagnosis of AMI is imperative for the subsequent disease treatment, yet it presents substantial challenges. After AMI, the myocardium typically exhibits elevated levels of peroxynitrite (ONOO-), constituting a distinct microenvironmental feature. In this context, the near-infrared imaging probe (BBEB) is employed to precisely delineate the boundaries of AMI lesions with a high level of sensitivity and specificity by monitoring endogenous ONOO-. This probe allows for the early detection of myocardial damage at cellular and animal levels, providing exceptional temporal and spatial resolution. Notably, BBEB enables visualization of ONOO- level alterations during AMI treatment incorporating antioxidant drugs. Overall, BBEB can rapidly and accurately visualize myocardial injury, particularly in the early stages, and can further facilitate antioxidant drug screening.

RNA modifications in cardiovascular diseases, the potential therapeutic targets.

More than one hundred RNA modifications decorate the chemical and topological properties of these ribose nucleotides, thereby executing their biological functions through post-transcriptional regulation. In cardiovascular diseases, a wide range of RNA modifications including m6A (N6-adenosine methylation), m5C (5-methylcytidin), Nm (2'-O-ribose-methylation), Ψ (pseudouridine), m7G (N7-methylguanosine), and m1A (N1-adenosine methylation) have been found in tRNA, rRNA, mRNA and other noncoding RNA, which can function as a novel mechanism in metabolic syndrome, heart failure, coronary heart disease, and hypertension. In this review, we will summarize the current understanding of the regulatory roles and significance of several types of RNA modifications in CVDs (cardiovascular diseases) and the interplay between RNA modifications and noncoding RNA, epigenetics. Finally, we will focus on the potential therapeutic strategies by using RNA modifications.