Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Lu, Qing-Bo¹  Wang, Hui-Ping²  Tang, Zi-Han²  Cheng, Han²  Du, Qiong²  Wang, Yuan-Ben²  Feng, Wu-Bing²  Li, Ke-Xue³  Cai, Wei-Wei²  Qiu, Li-Ying²  Sun, Hai-Jian² 

[1] Southeast Univ, Sch Med, Affiliated ZhongDa Hosp, Dept Neurol, Nanjing 210009, Jiangsu, Peoples R China

[2] Jiangnan Univ, Wuxi Sch Med, Dept Basic Med, 1800 Lihu Ave, Wuxi 214122, Jiangsu, Peoples R China

[3] Xuzhou Med Univ, Dept Physiol, Xuzhou 221004, Jiangsu, Peoples R China

关键词: Hypertension;    Nesfatin-1;    VSMCs;    Phenotypic transformation;    Vascular remodeling;   

DOI  :  10.1016/j.bbadis.2018.04.002

来源: Elsevier

【 摘 要 】

The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.

【 授权许可】

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