Restoration of Cullin3 gene expression enhances the improved effects of sonic hedgehog signaling activation for hypertension and attenuates the dysfunction of vascular smooth muscle cells
-
Published:2022-06-17
Issue:1
Volume:21
Page:
-
ISSN:1475-925X
-
Container-title:BioMedical Engineering OnLine
-
language:en
-
Short-container-title:BioMed Eng OnLine
Author:
Shen Jian,Li Youqi,Li Menghao,Li Zhiming,Deng Huantang,Xie Xiongwei,Liu Jinguang
Abstract
Abstract
Background
Hypertension is known as a major factor for global mortality. We aimed to investigate the role of Cullin3 (CUL3) in the regulation of hypertension.
Material and methods
Human vascular smooth muscle cells (VSMCs) were treated with Angiotensin II (Ang II) to establish a hypertension in vitro model. Cell viability was detected by a cell counting kit-8 (CCK-8) assay. The content of reactive oxygen species (ROS) was evaluated by kit. Transwell assay and TUNEL staining were, respectively, used to assess cell migration and apoptosis. Additionally, the expression of sonic hedgehog (SHH) signaling-related proteins (SHH, smoothened homolog (Smo) and glioblastoma (Gli)) and CUL3 was tested with western blotting. Following treatment with Cyclopamine (Cycl), an inhibitor of SHH signaling, in Ang II-induced VSMCs, cell viability, migration, apoptosis and ROS content were determined again. Then, VSMCs were transfected with CUL3 plasmid or/and treated with sonic hedgehog signaling agonist (SAG) to explore the impacts on Ang II-induced VSMCs damage. In vivo, a hypertensive mouse model was established. Systolic blood pressure and diastolic blood pressure were determined. The histopathologic changes of abdominal aortic tissues were examined using H&E staining. The expression of SHH, Smo, Gli and CUL3 was tested with western blotting.
Results
Significantly increased proliferation, migration and apoptosis of VSMCs were observed after Ang II exposure. Moreover, Ang II induced upregulated SHH, Smo and Gli expression, whereas limited increase in CUL3 expression was observed. The content of ROS in Ang II-stimulated VSMCs presented the same results. Following Cycl treatment, the high levels of proliferation and migration in Ang II-treated VSMCs were notably remedied while the apoptosis and ROS concentration were further increased. Moreover, Cycl downregulated SHH, Smo, Gli and CUL3 expression. Above-mentioned changes caused by Ang II were reversed following SAG addition. Indeed, SAG treatment combined with restoration of CUL3 expression inhibited proliferation, migration, apoptosis and ROS level in Ang II-stimulated VSMCs. In vivo, SAG aggravated the histopathological changes of the aorta and with a worse tendency after both SAG intervention and CUL3 silencing. By contrast, SAG treatment and rebound in CUL3 expression alleviated the vascular damage.
Conclusions
Collectively, restoration of CUL3 gene expression protected against hypertension through enhancing the effects of SHH activation in inhibition of apoptosis and oxidative stress for hypertension and alleviating the dysfunction of VSMCs.
Funder
Medical Scientific Research of Guangdong Province, China
Publisher
Springer Science and Business Media LLC
Subject
Radiology, Nuclear Medicine and imaging,Biomedical Engineering,General Medicine,Biomaterials,Radiological and Ultrasound Technology
Reference37 articles.
1. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217–23. 2. Wang Y, Zhang X, Gao L, Li JH, Chen WJ, Chi JY, Zhang XH, Fu Y, Zhao M, Liu N, et al. Cortistatin exerts antiproliferation and antimigration effects in vascular smooth muscle cells stimulated by Ang II through suppressing ERK1/2, p38 MAPK, JNK and ERK5 signaling pathways. Ann Transl Med. 2019;7(20):10. 3. Nour-Eldine W, Ghantous CM, Zibara K, Dib L, Issaa H, Itani HA, El-Zein N, Zeidan A. Adiponectin attenuates angiotensin ii-induced vascular smooth muscle cell remodeling through nitric oxide and the RhoA/ROCK pathway. Front Pharmacol. 2016;7:15. 4. Lu J, Lu Y, Wang X. Prevalence awareness treatment and control of hypertension in China data from 1.7 million adults in a population based screening study (vol 390, pg 2549, 2017). Lancet. 2017;390(10112):2548–2548. 5. Lou M, Zong XF, Wang LL. Curative treatment of hypertension by physical exercise. Eur Rev Med Pharmacol Sci. 2017;21(14):3320–6.
|
|