Myocardial infarction is the leading cause of end-stage heart failure. While drug intervention and coronary intervention have enabled patients with myocardial infarction to receive effective reperfusion therapy in a timely manner, these methods do not address the loss of necrotic cardiomyocytes at the "source," resulting in high mortality rates among patients with end-stage heart failure following myocardial infarction [1–3]. The reduction in cardiomyocyte numbers due to irreversible necrosis and apoptosis is the underlying cause of heart failure after myocardial infarction. Therefore, myocardial regeneration to enhance repair after myocardial infarction represents the fundamental approach for preventing and treating heart failure subsequent to myocardial infarction.
Previously, it was believed that the adult mammalian heart was a terminally differentiated organ that permanently exited the cell cycle and lost its regenerative capacity after reaching adulthood [4]. However, recent studies have challenged this notion by demonstrating the strong regenerative capacity of the heart in lower vertebrates and newborn mammals [5, 6]. Further research has revealed that adult cardiomyocytes also possess the potential for proliferation and self-renewal, albeit at a low rate [7]. To increase the number of cardiomyocytes, there are four major approaches that have been explored: exogenous stem cell transplantation, cellular reprogramming, tissue engineering, and endogenous myocardial regeneration [8, 9]. These approaches aim to either introduce new cardiomyocytes into the heart or stimulate the existing cardiomyocytes to proliferate and regenerate.
Gene targeted therapy for promoting endogenous myocardial regeneration involves the manipulation of target genes to regulate the expression of specific proteins, thereby stimulating quiescent cardiomyocytes to re-enter the cell cycle and promote cardiomyocyte proliferation for the repair of damaged myocardium. Previous studies have shown that the overexpression of cyclin D2 and cyclin A2 in the hearts of rats with myocardial infarction can induce cardiomyocyte proliferation and facilitate the repair of scarred areas following myocardial infarction [10, 11].
Furthermore, other studies have identified 40 miRNAs that effectively increase cardiomyocyte division in neonatal rats. Notable examples include miR-199a, miR-99p, and miR-128, which have been shown to promote cardiomyocyte re-entry into the cell cycle and facilitate myocardial regeneration in both neonatal and adult rats [12–14]. These findings highlight the potential of miRNAs as therapeutic targets for promoting endogenous myocardial regeneration.
Circular RNA (circRNA) is a type of non-coding RNA molecule that forms a closed loop structure without a 5' cap structure and a 3' poly(A) tail. It is primarily located in the cytoplasm or stored in exosomes [15]. Compared to traditional linear RNA, circRNA is more stable and resistant to degradation as it is not affected by RNA exonucleases. It has been found to be widely present in various eukaryotes. circRNAs play important roles in cardiac development and the progression of cardiovascular diseases. For example, circ-Amotl1 has been shown to promote AKT protein phosphorylation and nuclear translocation, thereby reducing myocardial apoptosis and ventricular remodeling after myocardial infarction [16]. Another circRNA, circSlc8a1, can affect the expression of serum response factor Srf, connective tissue growth factor Ctgf, and adrenergic receptor Adrb1 by sequestering mir-133, thereby alleviating cardiac hypertrophy [17]. These findings highlight the significant impact of circRNAs on heart development and the prevention and treatment of cardiovascular diseases. They also suggest that circRNA may serve as a novel target for gene therapy in myocardial regeneration following myocardial infarction.
The main mechanism of circRNAs involves their function as endogenous competing RNAs (ceRNAs). As ceRNAs, circRNAs regulate gene expression through a common mode of gene regulation. Specifically, circRNAs can act as ceRNAs by competing with microRNA response elements to regulate the expression level of microRNAs, thereby influencing cellular functions. In our previous study, we discovered that circSorbs1 can bind to two isoforms of mmu-miR-99, namely mmu-miR-99a-3p and mmu-miR-99b-3p. It has been shown that miR-99 can induce proliferation in dedifferentiated cardiomyocytes by regulating Gata4, a transcription factor associated with myocardial regeneration [14]. Gata4 primarily functions by promoting the expression of cell cycle factors, such as cyclin A2 and cyclin E1 [18, 19]. Based on these findings, we speculate that circSorbs1 acts as a ceRNA by sequestering miR-99, thereby influencing the Gata4/cyclin signaling axis and mediating myocardial regeneration.