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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Inflammation Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1539690
This article is part of the Research Topic The Mechanisms of Fibrotic Disorders and Pharmacological Therapies View all 10 articles

Roles of Retinoic Acid-Related Orphan Receptor α in High Glucose-Induced Cardiac Fibroblasts Proliferation

Provisionally accepted
Wenqing San Wenqing San Qianyou Zhou Qianyou Zhou Danning Shen Danning Shen Danyi Cao Danyi Cao Yun Chen Yun Chen *Guoliang Meng Guoliang Meng *
  • Nantong University, Nantong, China

The final, formatted version of the article will be published soon.

    Diabetic cardiomyopathy, characterized by myocardial fibrosis, is a common complication of diabetes. Retinoic acid-related orphan receptor α (RORα) participates in various pathological and physiological cardiovascular processes. The current research aims to elucidate the roles and mechanisms of RORα in high glucose induced cardiac fibroblasts proliferation. Primary neonatal cardiac fibroblasts were isolated from Sprague-Dawley rats, and pre-administrated with RORα antagonist SR3335 (20 µM) or RORα agonist SR1078 (10 µM) followed by the stimulation with normal glucose (5.5 mM) or high glucose (33.3mM) respectively. Lactate Dehydrogenase (LDH) release into culture medium, cellular adenosine-triphosphate (ATP), and cell number were detected. Expressions of Collagen I, Collagen III, proliferating cell nuclear antigen (PCNA), α-smooth muscle actin (α-SMA), receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3) were evaluated. The extent of oxidative stress was also assessed. Our study found that high glucose elevated LDH release, reduced cellular ATP production, increased cells numbers, elevated expression of Collagen I, Collagen III, PCNA, α-SMA, RIPK1 and RIPK3, decreased mitochondrial membrane potential, strengthened intensity of dihydroethidium (DHE) and MitoSOX fluorescence. Above effects were all further exacerbated by SR3335 but significantly reversed by SR1078. In conclusion, RORα antagonist SR3335 promoted cell injury and proliferation, enhanced collagen synthesis, facilitated oxidative stress and necroptosis in cardiac fibroblasts with high glucose stimulation, whereas RORα agonist SR1078 showed opposing effects. Our study proposed RORα as a novel target against high glucose-induced cardiac fibroblasts proliferation, which is beneficial to clarify ideal therapeutic implication for diabetic cardiomyopathy.

    Keywords: cardiac fibroblasts, Retinoic acid-related orphan receptor α, proliferation, necroptosis, Oxidative Stress

    Received: 04 Dec 2024; Accepted: 13 Jan 2025.

    Copyright: © 2025 San, Zhou, Shen, Cao, Chen and Meng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yun Chen, Nantong University, Nantong, China
    Guoliang Meng, Nantong University, Nantong, China

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