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Published on: January 21, 2018
MiR-24-3p modulates cardiac function in doxorubicin -induced heart failure via the Sp1/PI3K signaling pathway
Yonghong Zheng1, Guojian Xiang1, Linwen Zeng2
1Provincial Clinical Medical College of Fujian Medical University, Fuzhou 350001, Fujian, China; Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, Fujian, China; Department of Cardiology, Fujian Provincial Hospital, Fuzhou 350001, Fujian, China.
Insights
Silencing microRNA-24-3p (miR-24-3p) protects against heart failure by activating the specificity protein 1 (Sp1)/phosphoinositide 3-kinase (PI3K) pathway, mitigating doxorubicin-induced damage.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Biochemistry
Background:
- Heart failure (HF) is a complex clinical syndrome with significant morbidity and mortality.
- MicroRNAs (miRNAs) play crucial roles in cardiovascular regulation, and dysregulation of specific miRNAs is implicated in HF pathogenesis.
- The role of miR-24-3p in doxorubicin (Dox)-induced cardiotoxicity and its downstream signaling pathways remains incompletely understood.
Purpose of the Study:
- To investigate the role of miR-24-3p in doxorubicin (Dox)-induced heart failure (HF).
- To elucidate the impact of miR-24-3p on the specificity protein 1 (Sp1)/phosphoinositide 3-kinase (PI3K) signaling pathway in the context of HF.
- To explore the therapeutic potential of modulating miR-24-3p in HF.
Main Methods:
- Establishment of Dox-induced rat and H9c2 cardiomyocyte HF models.
- Assessment of cardiac function (echocardiography) and cardiac histology (HE staining).
- Investigation of molecular mechanisms using Sp1/PI3K inhibitors, miR-24-3p overexpression/silencing, ELISA, TUNEL, LDH assays, flow cytometry, qRT-PCR, Western blotting, and dual-luciferase assays.
Main Results:
- Dox treatment induced significant cardiac dysfunction, cardiomyocyte damage, apoptosis, and oxidative stress, accompanied by elevated miR-24-3p and reduced Sp1/PI3K expression.
- Inhibition of Sp1 or PI3K exacerbated Dox-induced cardiotoxicity, with reciprocal suppression of Sp1 and PI3K.
- Overexpression of miR-24-3p worsened Dox-induced damage, while silencing miR-24-3p conferred protection by upregulating Sp1/PI3K, and dual-luciferase assays confirmed direct targeting of Sp1 by miR-24-3p.
Conclusions:
- Doxorubicin induces cardiomyocyte damage and cardiac dysfunction through mechanisms involving miR-24-3p.
- Silencing miR-24-3p demonstrates a protective effect in heart failure.
- The protective effect of miR-24-3p silencing is mediated via the activation of the Sp1/PI3K signaling pathway.
Purpose:
The goal of this research was to explore the role of miR-24-3p in heart failure (HF), with a focus on its impact on the specificity protein 1 (Sp1)/phosphoinositide 3-kinase (PI3K) pathway.
Methods:
HF rat and HF cell models were established using doxorubicin(Dox). Cardiac function was assessed through echocardiography, while histological changes were observed via hematoxylin-eosin (HE) staining. To further investigate the underlying mechanisms, HF cell models were treated with either an Sp1 inhibitor or a PI3K inhibitor. Additionally, models with miR-24-3p overexpression or silencing were constructed. N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined by ELISA. Cell apoptosis was evaluated using TUNEL staining, and lactate dehydrogenase (LDH) levels were measured by colorimetry. Reactive oxygen species (ROS) production was analyzed using flow cytometry. Related gene and protein expressions were assessed via qRT-PCR and Western blotting. Finally, the relationship between miR-24-3p and Sp1 was confirmed through dual-luciferase assays.
Results:
Dox treatment increased the left ventricular internal diameter (LVIDd) while decreasing ejection fraction (EF) and fractional shortening (FS), leading to disorganized cardiomyocyte arrangement, cellular edema, and necrosis in rats. In HF rats, NT-proBNP, Caspase-3, and miR-24-3p expression levels were elevated, whereas Sp1 and PI3K mRNA and protein expression levels were decreased. Similarly, Dox-induced damage in H9c2 cardiomyocytes resulted in increased NT-proBNP, apoptosis, Caspase-3, LDH, ROS, and miR-24-3p expression, along with decreased Sp1 and PI3K expression. Treatment with either Sp1 or PI3K inhibitors exacerbated the Dox-induced cardiomyocyte damage, further elevating NT-proBNP, apoptosis, Caspase-3, LDH, ROS, and miR-24-3p expression levels. Notably, Sp1 inhibition reduced PI3K expression, and PI3K inhibition, in turn, suppressed Sp1 expression. Overexpression of miR-24-3p worsened Dox-induced cardiomyocyte damage, characterized by increased NT-proBNP, apoptosis, Caspase-3, LDH, and ROS expression, alongside reduced Sp1 and PI3K expression. In contrast, silencing miR-24-3p mitigated these detrimental effects and increased Sp1 and PI3K expression. Dual-luciferase assays confirmed that miR-24-3p directly targets Sp1.
Conclusion:
Dox induces cardiomyocyte damage, impairs cardiac function, and promotes cardiomyocyte apoptosis and oxidative stress. Silencing miR-24-3p offers a protective effect by activating the Sp1/PI3K signaling pathway in heart failure.
