Retinoid X receptor agonists alleviate fibroblast activation and post-infarction cardiac remodeling via inhibition of TGF-β1/Smad pathway

• Published in: Life sciences (1973) 2023-09, Vol.329, p.121936-121936, Article 121936
• Main Authors: Lin, Xiao-yan, Chu, Yong, Zhang, Guo-shan, Zhang, Hai-lin, Kang, Kai, Wu, Min-Xia, Zhu, Jiang, Xu, Chang-sheng, Lin, Jin-xiu, Huang, Chun-kai, Chai, Da-jun
• Format: Article
• Language: English
• Subjects: Fibroblast; Fibrosis; Myocardial infarction; Remodeling; Retinoid X receptor
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2023.121936

Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction (MI) remains unclear. This study aimed to determine the effects of RXR agonists on MI and to dissect the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to MI and then treated (once daily for 4 weeks) with either RXR agonist bexarotene (10 or 30 mg/kg body weight) or vehicle. Heart function was determined using echocardiography and cardiac hemodynamic measurements. Four weeks post MI, myocardial tissues were collected to evaluate cardiac remodeling. Primary cardiac fibroblasts (CFs) were treated with or without RXR ligand 9-cis-RA followed by stimulation with TGF-β1. Immunoblot, immunofluorescence, and co-immunoprecipitation were performed to elucidate the regulatory role of RXR agonists in TGF-β1/Smad signaling. In vivo treatment with Bexarotene moderately affects systemic inflammation and apoptosis and ameliorated left ventricular dysfunction after MI in rat model. In contrast, bexarotene significantly inhibited post-MI myocardial fibrosis. Immunoblot analysis of heart tissue homogenates from MI rats revealed that bexarotene regulated the activation of the TGF-β1/Smad signaling pathway. In vitro, 9-cis-RA inhibited the TGF-β1-induced proliferation and collagen production of CFs. Importantly, upon activation by 9-cis-RA, RXRα interacted with p-Smad2 in cytoplasm, inhibiting the TGF-β1-induced nuclear translocation of p-Smad2, thereby negatively regulating TGF-β1/Smad signaling and attenuating the fibrotic response of CFs. These findings suggest that RXR agonists ameliorate post-infarction myocardial fibrosis, maladaptive remodeling, and heart dysfunction via attenuation of fibrotic response in CFs through inhibition of the TGF-β1/Smad pathway activation. [Display omitted] •RXR agonist alleviates myocardial fibrosis, maladaptive remodeling, and heart dysfunction in rats with MI.•RXR agonist negatively regulates TGF-β1/Smad signaling and attenuating the proliferation and activation of cardiac fibroblasts.•RXR agonists may serve as a novel therapeutic candidate for the treatment of maladaptive remodeling for MI.