Apocynum venetum leaf extract alleviated doxorubicin-induced cardiotoxicity by regulating organic acid metabolism in gut microbiota

Zhenxiong Zhao; Shenglu Jiang; Qing Fan; Kuo Xu; Yubin Xu; Feiqiang Wu; Xihong Zhang; Ting Wang; Zhelin Xia

doi:10.3389/fphar.2023.1286210

Apocynum venetum leaf extract alleviated doxorubicin-induced cardiotoxicity by regulating organic acid metabolism in gut microbiota

Front Pharmacol. 2023 Nov 23:14:1286210. doi: 10.3389/fphar.2023.1286210. eCollection 2023.

Authors

Zhenxiong Zhao¹, Shenglu Jiang^{1

2}, Qing Fan³, Kuo Xu⁴, Yubin Xu¹, Feiqiang Wu², Xihong Zhang⁵, Ting Wang², Zhelin Xia¹

Affiliations

¹ Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China.
² School of Medicine, Taizhou University, Taizhou, Zhejiang, China.
³ Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
⁴ Marine Traditional Chinese Medicine Research Center, Shandong University of Traditional Chinese Medicine, Jinan, China.
⁵ Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang, China.

Abstract

Apocynum venetum leaf is commonly utilized for its beneficial effects in reducing blood pressure, inducing sedation, promoting diuresis, anti-aging, and cardioprotection, which also exhibit positive effects on the gut microbiota. The gut microbiota plays a role as an endocrine organ by producing bioactive metabolites that can directly or indirectly impact host physiology, specifically cardiovascular diseases. In this study, main chemical components of A. venetum leaf extract (AVLE) were identified by LC-MS, and an orally administered AVLE was employed to treat mice with doxorubicin (Dox)-induced cardiotoxicity. The results showed that AVLE contained hyperoside and oganic acids. The pharmacological findings revealed that AVLE regulated the gut microbiota, resulting in a significant increase in the levels of two organic acids, indole-3-propionic acid (IPA) and acetic acid (AA). Both IPA and AA exhibited the ability to reduce BNP, CK, and LDH levels in mice with Dox-induced cardiotoxicity. Moreover, IPA demonstrated an improvement in Dox-induced cardiac injury by inhibiting apoptosis, while AA promoted increased secretion of ghrelin through the parasympathetic nervous system, subsequently reducing cardiac fibrosis by decreasing collagen I, collagen III, and activin A. Hence, our study demonstrates that AVLE exerts a beneficial cardioprotective effect by modulating the gut microbiota, providing a potential novel target for the treatment and prevention of Dox-induced cardiotoxicity.

Keywords: Apocynum venetum leaf; cardiotoxicity; doxorubicin; gut microbiota; indole-3-propionic acid.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by National Natural Science Foundation of China (32200095), Natural Science Foundation of Shandong Province (ZR2021QH094), Zhejiang Provincial Natural Science Foundation of China (LQ22H280014), Zhejiang Provincial Medical and Health Science and Technology Plan Project (2023RC111) and Zhejiang Province Traditional Chinese Medicine science and technology plan project (2022ZB390).