PRMT1 alleviates isoprenaline-induced myocardial hypertrophy by methylating SRSF1

Abstract

Myocardial hypertrophy (MH) is an important factor contributing to severe cardiovascular disease. Previous studies have demonstrated that specific deletion of the protein arginine methyltransferase 1 (PRMT1) leads to MH, but the exact mechanism remains unclear. Serine/arginine-rich splicing factor 1 (SRSF1) affects the development and progression of cardiovascular disease by selectively splicing downstream signaling proteins. The present study is designed to determine whether PRMT1 is involved in MH by regulating SRSF1 and, if so, to explore the underlying mechanisms. Adult male mice and H9C2 cardiomyocytes are treated with isoprenaline (ISO) to establish MH models. The expression levels of PRMT1 are significantly decreased in the ISO-induced MH models, and inhibiting PRMT1 worsens MH, whereas overexpression of PRMT1 ameliorates MH. SRSF1 serves as the downstream target of PRMT1, and its expression is markedly elevated in MH. Moreover, SRSF1 increases the mRNA expressions of CaMKIIδ A and CaMKIIδ B, decreases the mRNA expression of CaMKIIδ C by altering the selective splicing of CaMKIIδ, and further participates in MH. In addition, there is an interaction between PRMT1 and SRSF1, whereby PRMT1 reduces the phosphorylation level of SRSF1 via methylation, thus further altering its functional activity and eventually improving MH. Our present study demonstrates that PRMT1 relieves MH by methylating SRSF1, which is expected to provide a new theoretical basis for the pathogenic mechanism of MH and potential drug targets for reducing MH and associated cardiovascular disease.

1. Introduction

Cardiovascular disease is the number one killer of human health [1]. According to the latest epidemiologic data, the incidence and mortality of cardiovascular disease are experiencing a constantly rising phase, and two of every five deaths are from cardiovascular disease [2]. Myocardial hypertrophy (MH) is the pathologic basis of multiple major cardiovascular diseases, such as hypertension, coronary heart disease (CHD), and heart failure (HF) [3]. The currently available preventive and therapeutic means for MH are inadequate to solve all clinical problems, suggesting that some unknown pathogenic factors exist in MH.

In recent years, increasing evidence has demonstrated that epigenetic mechanisms play important roles in the pathophysiology of MH [4]. Protein arginine methylation is a common epigenetic modification that may alter gene expression by transferring methyl groups to the guanidine nitrogen atom. Protein arginine methyltransferase 1 (PRMT1) is one of the main protein arginine methyltransferases (PRMTs) [5]. Previous studies have confirmed that cardiac-specific PRMT1 deletion leads to MH [6], suggesting that PRMT1 is closely associated with the development and progression of MH, but the exact mechanism has not been identified. Research has verified that serine/arginine-rich splicing factor 1 (SRSF1), a type of selective splicing factor, contributes to the diversity and complexity of proteomics by affecting gene expression, whereas abnormal splicing may produce severe pathological consequences [7]. Although substantial evidence indicates that aberrant protein selective splicing is related to MH, in which SRSF1 is involved in cardiovascular disease by selectively splicing downstream signaling proteins [8], whether PRMT1 affects MH by regulating SRSF1 remains largely unknown.