Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway

Xiaoyu Liu; An Chen; Qingchun Liang; Xiulin Yang; Qianqian Dong; Mingwei Fu; Siyi Wang; Yining Li; Yuanzhi Ye; Zirong Lan; Yanting Chen; Jing-Song Ou; Pingzhen Yang; Lihe Lu; Jianyun Yan

doi:10.1111/acel.13377

Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway

Aging Cell. 2021 Jun;20(6):e13377. doi: 10.1111/acel.13377. Epub 2021 May 9.

Authors

Xiaoyu Liu^{1

2

3}, An Chen^{1

2

3}, Qingchun Liang⁴, Xiulin Yang^{1

2

3}, Qianqian Dong^{1

2

3}, Mingwei Fu^{1

2

3}, Siyi Wang^{1

2

3}, Yining Li^{1

2

3}, Yuanzhi Ye^{1

2

3}, Zirong Lan^{1

2

3}, Yanting Chen⁵, Jing-Song Ou⁶, Pingzhen Yang^{1

2

3}, Lihe Lu⁵, Jianyun Yan^{1

2

3}

Affiliations

¹ Department of Cardiology, Laboratory of Heart Center, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
² Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, China.
³ Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, China.
⁴ Department of Anesthesiology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
⁵ Department of Pathophysiolgy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
⁶ Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

Abstract

Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular calcification is a gene-regulated biological process resembling osteogenesis involving osteogenic differentiation. However, there is no efficient treatment available for vascular calcification so far. The natural polyamine spermidine has been demonstrated to increase life span and protect against cardiovascular disease. It is unclear whether spermidine supplementation inhibits vascular calcification in CKD. Alizarin red staining and quantification of calcium content showed that spermidine treatment markedly reduced mineral deposition in both rat and human vascular smooth muscle cells (VSMCs) under osteogenic conditions. Additionally, western blot analysis revealed that spermidine treatment inhibited osteogenic differentiation of rat and human VSMCs. Moreover, spermidine treatment remarkably attenuated calcification of rat and human arterial rings ex vivo and aortic calcification in rats with CKD. Furthermore, treatment with spermidine induced the upregulation of Sirtuin 1 (SIRT1) in VSMCs and resulted in the downregulation of endoplasmic reticulum (ER) stress signaling components, such as activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP). Both pharmacological inhibition of SIRT1 by SIRT1 inhibitor EX527 and knockdown of SIRT1 by siRNA markedly blocked the inhibitory effect of spermidine on VSMC calcification. Consistently, EX527 abrogated the inhibitory effect of spermidine on aortic calcification in CKD rats. We for the first time demonstrate that spermidine alleviates vascular calcification in CKD by upregulating SIRT1 and inhibiting ER stress, and this may develop a promising therapeutic treatment to ameliorate vascular calcification in CKD.

Keywords: SIRT1; aging; chronic kidney disease; endoplasmic reticulum stress; spermidine; vascular calcification.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Humans
Male
Rats
Renal Insufficiency, Chronic / drug therapy*
Signal Transduction
Sirtuin 1 / metabolism
Spermidine / pharmacology
Spermidine / therapeutic use*
Vascular Calcification / drug therapy*

Substances

Sirtuin 1
Spermidine