Ischemic heart disease is the leading cause of cardiovascular death [1]. Unrelieved ischemia produces scar tissue and subsequently impairs global left ventricular contractile function, leading to progressive heart failure. Reperfusion has been demonstrated to reduce infarct size and improve cardiac function and survival rate [2]. However, reperfusion can also result in additional damage to the myocardium, which is known as ischemia/reperfusion (I/R) injury. After many years of effort, few interventions for reperfusion injury have successfully passed the proof-of-concept stage [2]. Hence, it is essential to investigate new therapeutic means for myocardial I/R injury treatment to help promote them from bench to bedside in a timely fashion.

The pathogenesis of myocardial I/R injury comprises apoptosis, autophagy, production of reactive oxygen species, mitochondrial dysfunction, and calcium overload [3]. Excessive apoptosis can aggravate myocardial ischemia and I/R injury [4]. The endoplasmic reticulum is the main storage location for Ca2+. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) has many subtypes, among which, SERCA2a plays a crucial role in the cardiovascular system. During the excitation-contraction coupling process of cardiomyocytes, SERCA2a pumps Ca2+ from the cytoplasm into the sarcoplasmic reticulum in an ATP-dependent inverse concentration gradient. If the expression or activity of SERCA2a decreases, a large amount of Ca2+ will remain in the cytoplasm, which is known as calcium overload. Calcium overload will then cause cardiomyocyte apoptosis, eventually leading to myocardial damage [5]. Many studies from around the world have verified that the expression of SERCA2a is significantly downregulated after myocardial I/R injury [[6], [7], [8], [9]], and that the increased expression of SERCA2a can effectively relieve apoptosis and reduce myocardial I/R injury [6].

Long non-coding RNAs (lncRNAs) are a large class of RNAs with a length of >200 nucleotides and without protein-coding properties. Numerous studies have shown that lncRNAs are pivotal regulators of varied cardiac diseases, including cardiac I/R injury, via their involvement in autophagy, mitochondrial dysfunction, and calcium overload [10], especially in apoptosis [[11], [12], [13], [14]]. Furthermore, lncRNAs can encode polypeptides to regulate the activity of SERCA2a in cardiomyocytes, thereby affecting cardiac function [15,16]. An in-depth understanding of the lncRNA mechanism in regulation of cardiovascular diseases can offer some new ideas for exploring the prevention and treatment measures for cardiovascular diseases.

LncRNA just proximal to XIST (JPX) is a molecular switch for X-chromosome inactivation that is very popular in tumor research [[17], [18], [19]]. However, an emerging study has shown that JPX overexpression promoted the proliferation of human nucleus pulposus cells and reduced their apoptosis [20]. Hence, JPX might take part in the process of alleviating myocardial cell apoptosis.

Recent studies have revealed that lncRNAs played a significant role in many life processes. They can be broadly divided into those that act in cis, influencing the expression and/or chromatin state of neighboring genes, and those that exert a range of functions in trans throughout the cell [21]. The Ensembl website shows that the JPX gene is located on chromosome X, while the SERCA2a gene is located on chromosome 5. Presently, trans regulation has become the focus of lncRNAs’ regulation of gene transcription and expression in the cytoplasm and nucleus in a variety of ways. Thus, JPX might regulate the expression of SERCA2a in trans.

The polycomb repressive complex 2 (PRC2) is one of the most intensively studied epigenetic modifiers that is usually associated with target gene silencing. As a framework, lncRNA has been reported to be able to regulate the transcription of target genes via binding to PRC2, which is currently one of the most widely studied trans regulation actions. Enhancer of zeste homolog 2 (EZH2), the core enzymatic catalytic subunit of PRC2, has been shown to be able to modify gene expression via trimethylation of Lys-27 in histone 3 (H3K27me3) [22]. Wang et al. have shown that lncRNA-Chaer negatively regulated PRC2 activity by binding to EZH2, inhibiting H3K27 methylation at the promoter region of the target gene H19 and thereby promoting cardiac hypertrophy [23]. Protein pulldown experiments showed that Chaer specifically pulled down EZH2, but not SUZ12, EED, or other components of PRC2, as compared to the negative controls [23]. EZH2 has been found to act as a master regulator of cell cycle progression [24], apoptosis, and autophagy [25]. A prior study has reported that lncRNA promoted cell proliferation and inhibited apoptotic cells by recruiting EZH2 [26].

The present study aimed to verify that JPX could alleviate myocardial apoptosis by improving SERCA2a expression via binding to EZH2, and thus attenuated I/R-induced acute cardiomyocyte damage.