circRNA Hipk3 Induces Cardiac Regeneration after Myocardial Infarction in Mice by Binding to Notch1 and miR-133a

Abstract

The synergism between cardiomyogenesis and angiogenesis is essential for cardiac regeneration. Circular RNAs (circRNAs) play pivotal roles in cell growth and angiogenesis, but their functions in cardiac regeneration are not yet known. In this study, we investigated the role and underlying mechanisms of circRNA Hipk3 (circHipk3) in both cardiomyogenesis and angiogenesis during cardiac regeneration. We found that circHipk3 was overexpressed in the fetal or neonatal heart of mice. The transcription factor Gata4 bound to the circHipk3 promoter and increased circHipk3 expression. Cardiomyocyte (CM) proliferation in vitro and in vivo was inhibited by circHipk3 knockdown and increased by circHipk3 overexpression. Moreover, circHipk3 overexpression promoted coronary vessel endothelial cell proliferation, migration, and tube-forming capacity and subsequent angiogenesis. More importantly, circHipk3 overexpression attenuated cardiac dysfunction and decreased fibrotic area after myocardial infarction (MI). Mechanistically, circHipk3 promoted CM proliferation by increasing Notch1 intracellular domain (N1ICD) acetylation, thereby increasing N1ICD stability and preventing its degradation. In addition, circHipk3 acted as a sponge for microRNA (miR)-133a to promote connective tissue growth factor (CTGF) expression, which activated endothelial cells. Our findings suggested that circHipk3 might be a novel therapeutic target for preventing heart failure post-MI.

CircHIPK3: Key Player in Pathophysiology and Potential Diagnostic and Therapeutic Tool

“…Furthermore, the overexpression of circHIPK3 promoted heart regeneration in adult mice. The circHipk3-miR-133a (the circHipk3-miR-133a-connective tissue growth factor axis) pathway in the myocardium participates in mediating the function and angiogenesis of human coronary artery endothelial cells (HCAECs) during infarction, while circHIPK3 induces cardiomyocyte proliferation by increasing the stability of notch1 intracellular domain (N1ICD) ( 23 ). Bai et al found that circHIPK3 promotes myocardial ischemia/reperfusion injury by sponge miR-124-3p ( 24 ).…”

Non‐coding RNAs in cardiomyocyte proliferation and cardiac regeneration: Dissecting their therapeutic values

“…79 CircHipk3 could increase the stability of Notch1 intracellular domain (N1CID) by acetylation and prevent its degradation to stimulate CMs proliferation. 79 CircHipk3 also acts as a sponge for miR-133a to increase the expression level of connective tissue growth factor (CTGF), then activates endothelial cells. 79 The summary of LncRNA and CircRNA in CMs proliferation are listed in Table 2.…”

“…79 CircHipk3 also acts as a sponge for miR-133a to increase the expression level of connective tissue growth factor (CTGF), then activates endothelial cells. 79 The summary of LncRNA and CircRNA in CMs proliferation are listed in Table 2. AAV9 has been widely used in rodents while AAV6 has been used to cure cardiac injury in pigs.…”

Circular RNAs in Cardiac Regeneration: Cardiac Cell Proliferation, Differentiation, Survival, and Reprogramming

“…CircHIPK3 is an example of a circRNA involved in cellular growth that has simultaneously been implicated in the growth, proliferation, and metastasis of cancer ( Zheng et al, 2016 ; Zeng et al, 2018 ). CircHIPK3 is also relatively abundant in the fetal and neonatal myocardium of mice ( Si et al, 2020 , p. 3). This motivated an investigation into its potential regeneration-inducing capacity in the myocardium in vitro and in vivo .…”

“…CircHIPK3 is perhaps the perfect example to illustrate the sheer multitude of effects that can be exhibited by a single circRNA. Si et al (2020) demonstrated that the overexpression adenoviral vector-associated circHIPK3 induces coronary artery endothelial proliferation, increases cardiomyocyte proliferation, promotes angiogenesis, and decreases fibrosis in the zone surrounding the infarction area in adult mice. Whereas the pro-angiogenic properties seem to be conveyed through a miRNA-133a sponging effect, the effects on the cardiomyocytes were found to be achieved through an increase in the stability of the Notch1 intracellular domain.…”