Abstract
The ceRNA network involving circular RNAs (circRNAs) is essential in the cardiovascular system. We investigated the underlying ceRNA network involving circHIPK3 in myocardial infarction (MI). After an MI model was established, cardiac function was verified, and myocardial tissue damage in mice with MI was evaluated. A hypoxia model of cardiomyocytes was used to simulate MI in vivo, and the expression of and targeting relationships among circHIPK3, miR-93-5p, and Rac1 were verified. The apoptosis of cardiomyocyte was identified. Gain- and loss-of-functions were performed to verify the ceRNA mechanism. The MI-modeled mice showed cardiac dysfunction and enlarged infarct size. CircHIPK3 was highly expressed in mouse and cell models of MI. Silencing circHIPK3 reduced infarct size, myocardial collagen deposition, and myocardial apoptosis rate and improved cardiac function. CircHIPK3 sponged miR-93-5p, and miR-93-5p targeted Rac1. Overexpression of miR-93-5p inhibited MI-induced cardiomyocyte injury and eliminated the harmful effect of circHIPK3. CircHIPK3 acted as ceRNA to absorb miR-93-5p, thus promoting the activation of the Rac1/PI3K/AKT pathway. We highlighted that silencing circHIPK3 can upregulate miR-93-5p and then inhibit the activation of Rac1/PI3K/Akt pathway, which can improve MI-induced cardiac dysfunction.
Highlights
Myocardial infarction (MI) is among the most serious health threats, which leads to dysfunction and irreversible loss of cardiomyocytes [1]
We highlighted that circHIPK3 as a ceRNA absorbed miR-93-5p and activated the Rac1/PI3K/AKT pathway
We revealed that circHIPK3 expression in myocardial tissue of myocardial infarction (MI) mice and in vitro cell model was significantly increased
Summary
Myocardial infarction (MI) is among the most serious health threats, which leads to dysfunction and irreversible loss of cardiomyocytes [1]. CircHIPK3/miR-93-5p/Rac in Myocardial Infarction post-traumatic stress disorder [4]. After an episode of MI, patients remain at risk for recurrent arrhythmia, heart failure, and sudden death [6]. Despite decades of therapeutic advances, MI remains a leading cause of death [8]. In such a context, it is urgent to search for effective molecular pathways to provide insight into the prevention and management of MI. Exosomal circHIPK3 secreted from hypoxic cardiomyocytes monitors oxidative damage in cardiac microvascular endothelial cells through the miR-29a/IGF-1 axis [17]. We speculated that circHIPK3 may regulate cell behavior in MI via interacting with miR to form a circRNA– miR–mRNA network. We performed a series of histological and molecular experiments to identify the circRNA– miR–mRNA network and to study the underlying molecular mechanism, with the purpose to provide some novel therapies against MI
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