Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs

Li，Ru Li1,2; Zhuo，Cai Li1; Yan，Xin1; Li，He1; Lin，Lan1; Li，Ling Yu1; Jiang，Qiying3; Zhang，Die1; Wang，Xue Mei1; Liu，Lin Ling1,3; Huang，Wen Jing1; Wang，Ying Ling1; Li，Xin Yue1; Mao，Yan1; Chen，Yixin1; Liu，Xiao1; Xu，Quan Chen4; Cai，Yu Yan5; Yang，Xi Jing6; Chen，Hong Ying1,6; Wu，Si Si1,6; Jiang，Wei1

2024

10.7150/ijbs.84153

International journal of biological sciences   影响因子和分区

1449-2288

1449-2288

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/β5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.

Calcium homeostasis ERS Hypertension Irisin Vascular remodeling

SCI

英语

ESI高被引

其他

National Natural Science Foundation of China["81900276","82270465","82070299","81870221","81670249","82102267"] ; Natural Science Foundation of Sichuan["2023NSFSC1470","2021YJ0218","2023NSFSC1473"] ; Dissemination and Application Project of the Sichuan Province Health Commission's popularization and application project[2020HXBH073] ; null[20PJ146]

Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics

Biochemistry & Molecular Biology ; Biology

WOS:001143491400007

IVYSPRING INT PUBL

2-s2.0-85181774816

Scopus

1.Molecular Medicine Research Center,State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu,610041,China
2.Sichuan Key Laboratory of TCM Regulating Metabolic Diseases,Affiliated Hospital of Chengdu University of Traditional Chinese Medicine,Chengdu University of Traditional Chinese Medicine,Chengdu,610072,China
3.West China College of Preclinical Medicine and Forensic Medicine,Sichuan University,Chengdu,610041,China
4.Department of Biomedical Engineering,Southern University of Science and Technology,518055,China
5.Department of Cardiology,West China Hospital,Sichuan University,Chengdu,610041,China
6.Core Facilities,West China Hospital,Sichuan University,Chengdu,610041,China

Li，Ru Li,Zhuo，Cai Li,Yan，Xin,et al. Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs[J]. International journal of biological sciences,2024,20(2):680-700.

Li，Ru Li.,Zhuo，Cai Li.,Yan，Xin.,Li，He.,Lin，Lan.,...&Jiang，Wei.(2024).Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs.International journal of biological sciences,20(2),680-700.

Li，Ru Li,et al."Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs".International journal of biological sciences 20.2(2024):680-700.