Adropin inhibits the phenotypic modulation and proliferation of vascular smooth muscle cells during neointimal hyperplasia by activating the AMPK/ACC signaling pathway

Li Wang; Liang-Ping Zhao; Yu-Qi Chen; Xian-Song Chang; Hui Xiong; Dai-Min Zhang; Wei-Ting Xu; Jian-Chang Chen

doi:10.3892/etm.2021.9992

Adropin inhibits the phenotypic modulation and proliferation of vascular smooth muscle cells during neointimal hyperplasia by activating the AMPK/ACC signaling pathway

Exp Ther Med. 2021 Jun;21(6):560. doi: 10.3892/etm.2021.9992. Epub 2021 Mar 26.

Authors

Li Wang^{1

2}, Liang-Ping Zhao¹, Yu-Qi Chen¹, Xian-Song Chang¹, Hui Xiong¹, Dai-Min Zhang³, Wei-Ting Xu¹, Jian-Chang Chen¹

Affiliations

¹ Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215151, P.R. China.
² Emergency Department, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215151, P.R. China.
³ Department of Cardiology, Nanjing First Hospital, Nanjing, Jiangsu 210006, P.R. China.

Abstract

In-stent restenosis (ISR) remains an inevitable problem for some patients receiving drug-eluting stent (DES) implantation. Intimal hyperplasia is an important biological cause of ISR. It has been previously reported that adropin is a potentially protective factor in cardiovascular disease. Therefore, the present study investigated the function of adropin in inhibiting smooth muscle cell (SMC) phenotype modulation and proliferation, causing intimal hyperplasia. A total of 56 patients who visited the hospital consecutively (25 with ISR and 31 without ISR), who were followed up between April 2016 and March 2019, 1 year following DES, were analyzed to evaluate the association between in-stent neointimal volume and adropin serum levels. Rat aorta smooth muscle cells (RASMCs) were used to determine the effects of adropin on their phenotypic modulation and proliferation using western blot, MTT, PCR and immunofluorescence analyses. Adropin serum levels in the ISR group were significantly lower than those in the non-ISR group. Furthermore, linear regression analysis revealed that only adropin levels were negatively associated with neointimal volume in both groups. The overall adropin levels of the 56 patients and the percentages of neointimal volume revealed a strong negative association. In vitro, adropin suppressed angiotensin II (Ang II)-induced phenotypic modulation in RASMCs by restoring variations of osteopontin and α-smooth muscle actin. Furthermore, compared with the Ang II group, adropin markedly decreased the percentage of G₂/M-phase cells. Finally, adropin negatively regulated the phenotypic modulation and proliferation of RASMCs via the AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) signaling pathway. In conclusion, an independent, negative association was revealed between adropin and intimal hyperplasia; specifically, adropin inhibited the phenotypic modulation and proliferation of RASMCs by activating the AMPK/ACC signaling pathway. Therefore, adropin may be used as a potential predictor and therapeutic target for intimal hyperplasia and ISR.

Keywords: AMP-activated protein kinase; acetyl-CoA carboxylase; adropin; in-stent restenosis; neointimal hyperplasia; phenotypic modulation; proliferation.

Grants and funding

Funding: The present study was funded by the Suzhou Science and Technology Development Program Guidance Project Fund (grant no. SYSD2013093), the Youth Natural Science Fund of Soochow University (grant no. SDY2013A32), Xinxin Heart (SIP) Foundation (2019-CCA-ACCESS-058), and the Research Fund of the Second Affiliated Hospital of Soochow University (grant no. SDFEYGJ1405).