RRM2 Improves Cardiomyocyte Proliferation after Myocardial Ischemia Reperfusion Injury through the Hippo-YAP Pathway

Abstract

Objective. Ribonucleotide reductase M2 (RRM2) as an enzyme that catalyzes the deoxyreduction of nucleosides to deoxyribonucleoside triphosphate (dNTP) has been extensively studied, and it plays a crucial role in regulating cell proliferation. However, its role in ischemia-reperfusion injury (I/RI) is still unclear. Methods. SD rats were used as the research object to detect the expression of RRM2 in the myocardium by constructing an I/RI model. At the same time, primary SD neonatal rat cardiomyocytes were extracted, and hypoxia/reoxygenation (H/R) treatment simulated the I/RI model. Using transfection technology to overexpress RRM2 in cardiomyocytes, quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of RRM2, Cell Counting Kit-8 (CCK-8) assay was used to detect cell viability, and immunofluorescence staining was used to detect Ki67 and EdU-positive cells. Western blot (WB) technology was used to detect YAP and its phosphorylation expression. Results. qRT-PCR results indicated that the expression of RRM2 was inhibited in the model group, and cardiomyocytes overexpressing RRM2 can obviously promote the proliferation of primary cardiomyocytes and improve the damage of cardiac structure and function caused by I/R. At the same time, RRM2 can promote the increase of YAP protein expression and the increase of Cyclin D1 mRNA expression. Conclusion. RRM2 expression was downregulated in myocardial tissue with I/R. After overexpression of RRM2, cardiomyocyte proliferation was upregulated and the Hippo-YAP signaling pathway was activated.

RRM2 regulates osteogenesis of mouse embryo fibroblasts via the Wnt/β‑catenin signaling pathway

“…RRM2 is known as a crucial enzyme involved in DNA synthesis and repair, which contributes to regulating cell proliferation and differentiation (26). By activating the hippo-yes-associated protein signaling pathway, RRM2 can enhance myocardial cell proliferation after myocardial ischemia reperfusion injury (19). RRM2 has the potential to be exploited as a tumor marker for lung and liver cancer, as well as a therapeutic target (18,27).…”

“…Previous studies (17)(18)(19)26,27) on RRM2 have mainly focused on cancer markers and cell proliferation. To the best of the authors' knowledge, the present study was the first to demonstrate that RRM2 enhanced osteogenic differentiation of MEFs, potentially by activating the canonical Wnt/β-catenin signaling pathway, providing a possible target for osteoporosis treatment.…”

“…It is important for controlling cell proliferation and differentiation (17). RRM2 can enhance cardiac myocyte proliferation and act as a tumor biomarker, according to most studies (18,19). However, to the best of the authors' knowledge, its significance in osteogenic differentiation remains to be elucidated.…”

N6-methyladenosine (m6A) RNA modification in the pathophysiology of heart failure: a narrative review

“…As another class of m6A regulator, WTAP suppressed ATF4 expression by increasing the m6A level of the ATF4 transcript, reducing hypoxia/reperfusion (H/R)-induced cell apoptosis and endoplasmic reticulum (ER) stress in AC16 cells ( 77 ). Furthermore, the FTO molecule can protect cardiomyocytes via increasing Yes-associated protein (YAP) mRNA stability ( 78 ); YAP is associated with proliferation and oncogenic activity ( 79 ). Collectively, this evidence indicates that alternation of m6A and m6A regulator could potentially be used to curb the damage caused by IRI.…”

STUB1 is acetylated by KAT5 and alleviates myocardial ischemia-reperfusion injury through LATS2-YAP-β-catenin axis

“…Hippo-YAP pathway activation exerts crucial roles in myocardial regeneration, which represents as an effective therapeutic strategy for MIRI 15 . Furthermore, Ube2s-mediated stabilization of β-catenin was proved to ameliorate MIRI in mice through activation of HIF-1α 16 .…”