Role of STK38L in atrial fibrillation-associated myocardial fibrosis: findings from RNA-seq analysis.

Abstract

Myocardial fibrosis is a key pathological feature of many cardiovascular diseases, leading to cardiac dysfunction. Transforming growth factor β1 (TGF-β1) induces the proliferation and activation of cardiac fibroblasts (CFs), key contributors to myocardial fibrosis. To explore the mechanism underlying myocardial fibrosis, we aimed to determine whether serine/threonine kinase 38 like (STK38L) contributes to the development of myocardial fibrosis by regulating the proliferation and activation of CFs triggered by TGF-β1. In this study, atrial tissue samples from atrial fibrillation (AF) patients with features of myocardial fibrosis (a category of atrial cardiomyopathy) and sinus rhythm (SR) patients without myocardial fibrosis were collected for RNA sequencing (RNA-seq). The specific molecule STK38L was identified. Primary mouse CFs were activated with TGF-β1 and subsequently transfected with STK38L-small interfering RNA (siRNA). The effect of STK38L-siRNA on fibroblast activation and proliferation was assessed using scratch and Cell Counting Kit-8 (CCK-8) assays. Furthermore, a mouse model of myocardial fibrosis induced by continuous subcutaneous injection of isoprenaline (ISO) was established to assess STK38L expression levels. Molecular experiments confirmed the expression of STK38L in fibrotic atrial tissues, ventricular tissues of ISO mouse, and primary CFs of neonatal mice. We identified 1,870 genes exhibiting differential expression in the RNA-seq data between the AF and SR groups. Masson's trichrome staining revealed increased fibrosis in the heart tissues of the AF group. Elevated levels of STK38L were observed in the atrial tissues of the AF group and in the TGF-β1-stimulated primary mouse CFs. In vitro, STK38L knockdown suppressed mouse CFs activation and proliferation. Additionally, in vivo experiments showed that elevated mRNA levels of STK38L, periostin (POSTN), and collagen type I alpha 1 chain (COL1A1) in ISO-treated mouse hearts correlated with greater myocardial fibrosis, suggesting that STK38L plays an important role in the development of fibrosis. This study revealed a significant correlation between increased STK38L expression and AF characterized by atrial fibrosis as well as between STK38L expression and the TGF-β1-related induction of myocardial fibrosis. Additionally, STK38L knockdown was shown to suppress CFs activation and proliferation under TGF-β1 stimulation. These findings suggest an important role of STK38L in the development of fibrosis, and help screen for new strategies to treat this complex disease.