LIPCAR, Cuproptosis, and Α-SMA in the Pathogenesis of AMI and Remodeling

Acute myocardial infarction (AMI) is a primary cause of high mortality and disability, which seriously threatens human health across the world (1). AMI is the result of acute interruption of myocardial blood flow followed by myocardial ischemic hypoxic necrosis changes (2). Generally speaking, the traditional risk factors include age, smoking, hypertension, obesity, diabetes, and family history (3). There are two main strategies to reduce the size of myocardial infarction, reduce mortality and improve the prognosis: an early opening of the infarcted vessel and restoration of myocardial blood perfusion, namely known as drug thrombolysis or percutaneous coronary intervention (PCI) surgery (4). Clinically, ECG and high-sensitive cardiac troponins are widely used diagnostic indicators of AMI (5). However, about one-third of patients still do not receive reperfusion therapy as early as possible due to their delayed diagnosis. Therefore, searching for potential biomarkers with high sensitivity and specificity at the beginning of AMI is of great value for individualized diagnosis, early interventional treatment and improvement of prognosis.

The potential use of long noncoding RNAs (LncRNAs) as new biomarkers for cardiovascular diseases is eliciting an increasing interest, because they can be easily detectable and quantifiable in blood samples and are more stable than proteins (6). LncRNAs are a type of transcription products longer than 200 nucleotides that lack protein coding capacity but can epigenetically control both gene expression and protein translation (7). Several lncRNAs were shown to be modulated in the heart or in the circulation in different stress conditions such as AMI and shown to be involved in cardiac remodeling by regulating many biological processes including hypertrophy, fibrosis, autophagy and apoptosis (8). LIPCAR (Long Intergenic noncoding RNA predicting CARdiac remodeling) was identified by Kumarswamy et al. as biomarker of cardiac remodeling" cardiac hypertrophy and fibrosis" and heart failure post-AMI (9). LIPCAR is also a potential biomarker in patients suffering from ST segment elevation myocardial infarction and heart failure post- AMI (10).

Copper is a crucial trace element that plays a role in various pathophysiological processes in the human body. Copper also acts as a transition metal involved in redox reactions, an overabundance of copper is pernicious to the cells, contributing to the generation of reactive oxygen species (ROS). Under prolonged and increased ROS levels, oxidative stress occurs, which has been implicated in different types of regulated cell death (11). The recent discovery of cuproptosis, a copper-dependent regulated cell death pathway that is distinct from other known regulated cell death forms, has raised interest to researchers to reinforce the concept that oxidative stress is a fundamental mechanism of metal-induced toxicity.

The underlying mechanism of copper-induced cell death was unclear until the article "Copper induces cell death by targeting lipoylated TCA cycle proteins" was published by Tsvetkov et al. in 2022. The study sheds light on a novel form of cell death known as cuproptosis, wherein copper binds directly to lipoylated components of the tricarboxylic acid (TCA) cycle, leading to lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss that in turn causes proteotoxic stress and ultimately cell death. The cuproptosis involved in the development of AMI may be dependent on mitochondrial dysfunction (12).

Cuproptosis -related genes (CRGs) were enriched in the regulation of reactive oxygen species metabolic processes, inflammatory response-related pathways, and lipid and atherosclerosis, implying that differential CRGs might participate in the initiation and progression of AMI through these biological processes. Most studies have demonstrated that inflammatory responses play an important role in the initiation and subsequent repair of myocardial infarction (13). Recent studies have linked CRGs: signal transducer and activator of transcription 3 (STAT3), DNA damage-inducible transcript 3 (DDIT3) and AMI, shedding new light on diagnosis and therapy (14, 15). During AMI, the upregulation of DDIT3, a pro-apoptotic transcriptional factor and a feature of endoplasmic reticulum (ER) stress, leads to increased apoptosis of myocardial cells (16). DDIT3 has been shown to have a close relationship with STAT3 in AMI (17).

The α-SMA (alpha-smooth muscle actin) protein plays a crucial role in the regulation of both the proliferation and remodeling of cardiomyocytes, which are the muscle cells of the heart in the first few hours after the onset of coronary occlusion. In the aftermath of a myocardial infarction, it is essential for the damaged heart muscle cells to undergo a process of repair and regeneration to restore normal heart function. Therefore, monitoring and evaluating α-SMA protein expression as a marker of cardiac recovery holds significant importance when assessing the prognosis of patients following acute myocardial infarction (18).

The pathophysiology of acute myocardial infarction is multifaceted, involving numerous biological processes. The crosstalk between cuproptosis and remodeling biomarkers may be implicated in the pathogenesis of AMI. Combining cuproptosis, LIPCAR, and α-SMA cardiac recovery analysis may enable more precise identification of diagnostic biomarkers that help for future improvement of treatment and prognosis.