Activating the PGC-1α/TERT Pathway by Catalpol Ameliorates Atherosclerosis via Modulating ROS Production, DNA Damage, and Telomere Function: Implications on Mitochondria and Telomere Link.

Yukun Zhang,Huijun Sun,Zhihao Liu,Qi Liu,Yue Jin,Lifei Cai,Kexin Liu,Qining Yang,Yongguo Dai,Changyuan Wang,Qiang Meng

doi:10.1155/2018/2876350

Yukun Zhang, Huijun Sun + Show 9 more

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https://doi.org/10.1155/2018/2876350

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Abstract

Catalpol, an iridoid glucoside, has been found present in large quantities in the root of Rehmannia glutinosa L. and showed a strong antioxidant capacity in the previous study. In the present work, the protective effect of catalpol against AS via inhibiting oxidative stress, DNA damage, and telomere shortening was found in LDLr−/− mice. This study also shows that activation of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/telomerase reverse transcriptase (TERT) pathway, which is the new link between mitochondria and telomere, was involved in the protective effects of catalpol. Further, by using PGC-1α or TERT siRNA in oxLDL-treated macrophages, it is proved that catalpol reduced oxidative stress, telomere function, and related DNA damage at least partly through activating the PGC-1α/TERT pathway. Moreover, dual luciferase activity assay-validated catalpol directly enhanced PGC-1α promoter activity. In conclusion, our study revealed that the PGC-1α/TERT pathway might be a possible therapeutic target in AS and catalpol has highly favorable characteristics for the treatment of AS via modulating this pathway.

Highlights

Atherosclerotic cardiovascular disease is a kind of agingrelated degenerative disease comprising of various disorders of the heart and blood vessels [1]
In order to elucidate the effect of catalpol on the development of AS, aortic lesions were measured by oil red O staining
We demonstrated a decrease of PGC-1α in both in vivo and in vitro AS models, and upregulating PGC-1α protein expression by catalpol attenuated AS plaque formation and cell oxidative stress

Summary

Introduction

Atherosclerotic cardiovascular disease is a kind of agingrelated degenerative disease comprising of various disorders of the heart and blood vessels [1]. Oxidative stress and aging were considered to be the major causes of inflammation, DNA damage, and telomere dysfunction and shortening [2,3,4,5]. Macrophage plays a pivotal role in swallowing the plaque accumulation of lipids and apoptotic cells, maintaining the dynamic balance within the plaque of AS. Effective therapeutic interventions against AS provided by pharmacotherapy via modulating macrophage ROS accumulation, DNA damage, and telomere function are still currently limited. PGC-1α modulates diverse biological processes, ranging from metabolism, oxidative stress resistance, inflammation, aging, and redox balance to apoptosis [6,7,8]. PGC-1α expression is profoundly repressed in AS, thereby increasing ROS accumulation and cell apoptosis [9,10,11]. The repression of PGC-1α expression during AS was found, its specific roles as well as the detailed mechanisms are largely unknown

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