CDC5L facilitates cardiomyocyte proliferation and ameliorates myocardial ischemia-reperfusion injury via modulation of the FGF10-YAP axis

Abstract

Myocardial infarction (MI) causes irreversible cardiomyocyte loss, creating a need for cardiac repair therapies. The role of cell division cycle 5-like (CDC5L), a cell cycle regulator, in cardiac repair is unknown. This study aims to define the role of CDC5L in mitigating ischemia-reperfusion (I/R) injury by assessing its impact on cardiomyocyte proliferation and apoptosis and to determine the mechanism involving the FGF10-YAP axis. We model cardiac injury using in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) in neonatal mouse cardiomyocytes and in vivo I/R in adult mice. To investigate CDC5L function, we modulate its expression via adenoviral or AAV9-mediated overexpression or knockdown. Proliferation markers (EdU+, Ki67+, pH3+), apoptosis (TUNEL staining, Bax/Bcl-2 ratio), and cardiac function (echocardiography) are assessed. Through transcriptomic screening, we identify CDC5L downstream targets and validate their functional roles using FGF10 knockdown rescue assays. We find that CDC5L is upregulated in the post-I/R murine myocardium. Its overexpression enhances cardiomyocyte proliferation, preserves cardiac function, reduces apoptosis, and diminishes infarct size. Transcriptomic analysis identifies FGF10 as a key downstream effector, and we confirm that CDC5L upregulates FGF10 expression. Notably, FGF10 knockdown reverses the proliferative and anti-apoptotic effects of CDC5L. Moreover, the CDC5L-mediated reduction in YAP phosphorylation is also dependent on FGF10, as this effect is abolished upon FGF10 knockdown. In conclusion, CDC5L attenuates cardiac I/R injury by promoting cardiomyocyte proliferation and inhibiting apoptosis through the FGF10-YAP pathway. This CDC5L-FGF10-YAP axis represents a promising therapeutic target to improve myocardial regeneration and recovery after myocardial infarction.

1. Introduction

Myocardial infarction (MI), a serious cardiovascular disease caused by sudden interruption of coronary blood flow, directly results in the loss of cardiomyocytes and triggers complex pathological processes, including myocardial remodelling and heart failure, ultimately leading to death [1,2]. At present, the treatment for myocardial infarction focuses mainly on ischemia-reperfusion (I/R) methods, such as percutaneous coronary intervention, coronary artery bypass grafting, and drug thrombolysis [3]. Although these methods improve the blood supply of ischemic myocardial tissue after MI, they do not rescue necrotic myocardial cells or regenerate reduced cardiomyocytes [4]. As the ultimate treatment, heart transplantation completely resolves severe heart failure caused by heart injury, but the lack of donors limits its clinical application [5].

Therefore, elucidating the endogenous mechanisms that reactivate cardiomyocyte proliferation and mitigate apoptosis represents a promising therapeutic avenue for improving cardiac repair after MI. A key characteristic of adult mammalian cardiomyocytes is their exit from the cell cycle and loss of proliferative function. Therefore, when the myocardium is subjected to ischemic injury, necrotic myocardial cells can not be replaced and repaired by newly formed normal myocardial cells, and the tissue in the infarcted area is replaced only by fibrous scars [6]. This fibrous scar tissue does not have normal myocardial function, resulting in severe damage to cardiac function. Numerous studies have shown that the hearts of newborn mice regenerate within 7 days after birth, but this regenerative ability is lost after 7 days, indicating that there is a brief window for effective regeneration of myocardial cells [7]. Scholars have extensively explored and overcome the limitations of the endogenous regeneration of myocardial cells outside the regenerative window from multiple perspectives. (1) Overexpression of the OSKM transcription factor in the adult myocardium for a short period of time induces cardiomyocyte dedifferentiation and reprogramming, allowing cardiomyocytes to re-enter the cell cycle, promote cardiac regeneration and promote repair after myocardial infarction [8]. (2) HMGCS2 overexpression increases the dedifferentiation and proliferation of adult myocardial cells after myocardial infarction to improve cardiac function, and HMGCS2 knockdown worsens cardiac function after myocardial infarction reperfusion. (3) Inhibition of succinate dehydrogenase (SDH) activity prolongs the regeneration window of neonatal mouse hearts and promotes myocardial regeneration and repair after myocardial infarction [9,10]. These findings indicate that expanding the myocardia