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Veronica anagallis-aquatica L. iridoid glycosides alleviate heart failure via metabolites homoveratrumic acid and 2-hydroxy-3,4-dimethoxybenzoic acid mediated by the gut microbiota
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Manjiong Wanga, Xiaobo Guoa, Hanfang Liua, Xiao Lia, Yue Yaoa, Qing Fua, Yu Jina, Shuaishuai Nib, Xiaokang Lia, Chaojiang Xiaoc, Bei Jiangc, Conglong Xiac, *, Jian Lia, d, e, *, Yixiang Xua, *
Acta Pharmaceutica Sinica B | 2025, 15(6) : 3338 - 3342
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Acta Pharmaceutica Sinica B | 2025, 15(6): 3338-3342
• LETTER TO THE EDITOR •
Veronica anagallis-aquatica L. iridoid glycosides alleviate heart failure via metabolites homoveratrumic acid and 2-hydroxy-3,4-dimethoxybenzoic acid mediated by the gut microbiota
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Manjiong Wanga, Xiaobo Guoa, Hanfang Liua, Xiao Lia, Yue Yaoa, Qing Fua, Yu Jina, Shuaishuai Nib, Xiaokang Lia, Chaojiang Xiaoc, Bei Jiangc, Conglong Xiac, *, Jian Lia, d, e, *, Yixiang Xua, *
Affiliations
  • aState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
  • bCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
  • cYunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from Western Yunnan, Institute of Materia Medica & College of Pharmacy, Dali University, Dali 671000, China
  • dKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China
  • eKey Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, China
doi: 10.1016/j.apsb.2025.04.005
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Iridoid glycosides  /  Heart failure  /  Gut microbiota  /  Metabolite  /  Homoveratrumic acid  /  2-Hydroxy-3,4-dimethoxybenzoic acid  /  Cardiac hypertrophy  /  HDAC2
Manjiong Wang, Xiaobo Guo, Hanfang Liu, Xiao Li, Yue Yao, Qing Fu, Yu Jin, Shuaishuai Ni, Xiaokang Li, Chaojiang Xiao, Bei Jiang, Conglong Xia, Jian Li, Yixiang Xu. Veronica anagallis-aquatica L. iridoid glycosides alleviate heart failure via metabolites homoveratrumic acid and 2-hydroxy-3,4-dimethoxybenzoic acid mediated by the gut microbiota[J]. Acta Pharmaceutica Sinica B, 2025 , 15 (6) : 3338 -3342 . DOI: 10.1016/j.apsb.2025.04.005
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To the Editor
Heart failure (HF) is a multifactorial-induced chronic cardiovascular disease characterized by high mortality rates and poor patient prognosis. While current therapeutic interventions may relieve symptoms and enhance survival rates, the 5-year survival rate for patients remains below 50%1. This limitation may stem from the fact that the underlying pathophysiological mechanisms of HF have not yet been fully elucidated. Currently, clinical drug therapy primarily involves polypharmacy (quadruple therapy).
The complex regulatory mechanisms required for major chronic diseases like HF are well-aligned with the multi-component and multi-target nature of Chinese herbs. Therefore, the exploration and development of Chinese herbs could emerge as a focal point in the quest for innovative therapeutic strategies for HF. In this study, the ethanol extract of Veronica anagallis-aquatica L., identified from an in-house library of 828 Chinese herbs, demonstrated significant anti-HF potential. Further component analysis revealed that a cluster of iridoid glycoside analogs (referred to as HL0877i) act as the principal anti-HF active ingredient in Veronica anagallis-aquatica L.
Subsequent analysis of the 16S rDNA gene sequencing data indicated that HL0877i induced a remodeling of the gut microbiota. Additionally, fecal microbiota transplantation (FMT) assays confirmed that HL0877i alleviated HF in a gut microbe-dependent manner, highlighting the gut microbiota's potential role in mediating the anti-HF effects of HL0877i. This finding is consistent with a growing body of research that highlights the potential of various Chinese herbs to influence the gut microbiota positively. However, there is a lack of research elucidating the specific compounds that are crucial in this process and the underlying mechanisms of treatment. Herein, we discovered that two key active metabolites, homoveratrumic acid (HVA) and 2-hydroxy-3,4-dimethoxybenzoic acid (2OH–VA), were increased in the intestinal environment regulated by HL0877i. Mechanistically, HVA and 2OH–VA attenuate cardiac dysfunction and hypertrophy by suppressing the HDAC2–KLF4/INPP5F–AKT–GSK3β signaling pathway. In conclusion, the present study provides new insight into the mechanism underlying the anti-HF efficacy of iridoid glycosides originating from the Chinese herb Veronica anagallis-aquatica L. by modulating the gut microbiota and influencing the production of two metabolites, HVA and 2OH–VA, providing substantial support for anti-HF therapy.
1.　 Iridoid glycosides (HL0877i) concentrated from Veronica anagallis-aquatica L. shows potential as an anti-HF therapeutic agent
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First, we screened 828 ethanol extracts of particular medicinal plants from an in-house library, which originated from endemic plants in the western region of Yunnan Province, China, to discover valuable Chinese herbs with cardiomyocyte protective effects. Among them, Veronica anagallis-aquatica L. ethanol extract was identified as the most active extract (HL0877). After confirming the anti-HF activity of HL0877in vivo and in vitro (Supporting Information Fig. S1), we further explored what components play a major role in the activity. The reported components of Veronica anagallis-aquatica L. mainly include iridoid glycosides, phenylethanoid glycosides, flavonoids, and steroids2. Herein, iridoid glycosides (HL0877i) were extracted and purified via preparative liquid chromatography. Verproside, catalposide, and picroside II were the predominant components in this novel enriched fraction, with their combined content increased from 10.1% to 59.9% (w/w; Fig. 1A). These three components protect cardiomyocytes from oxygen-glucose deprivation (OGD, Supporting Information Fig. S2). Additionally, 18 other components were inferred, mainly flavonoids, organooxygen compounds, cinnamic acids and derivatives, benzene and substituted derivatives, prenol lipids, and others (Supporting Information Fig. S3 and Table S1).
Subsequently, the cytoprotective effects of HL0877i were evaluated in the OGD injury model. We demonstrated that HL0877i has a comparable ability to HL0877 in enhancing cell viability and in reducing levels of reactive oxygen species and lactate dehydrogenase (Supporting Information Fig. S4A–S4C). Moreover, compared with HL0877, HL0877i had a superior anti-HF effect in vivo (Fig. 1B–E and Fig. S4D). HL0877i administration at 150 mg/kg significantly mitigated the decline in ejection fraction (EF) and fractional shortening (FS) in isoprenaline (ISO)-induced HF mice. At 600 mg/kg, it further alleviated myocardial damage and fibrosis, comparable to 1.2 g/kg of HL0877, suggesting the importance of iridoid glycosides in maintaining the cardioprotective effects. Additionally, a two-week repeat-dose toxicity study was performed to assess the safety profile of HL0877i. The results indicated no cumulative toxicity following sustained oral administration of HL0877i (6 g/kg, Supporting Information Fig. S5). In conclusion, HL0877i effectively enriched the active constituents and demonstrated a favorable safety profile.
2.　HL0877i exerted a protective effect against HF by reshaping the gut microbiome of mice
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Several cohort studies have reported that the changes in the gut microbial community are associated with poor prognosis of HF patients3. These findings offer a novel perspective to elucidate the therapeutic mechanisms of traditional Chinese herbs, which involve the modulation of gut microbiota as a therapy strategy to treat HF. In our study, 16S rDNA sequencing revealed that HL0877i not only decreased community diversity and richness (Supporting Information Fig. S6A–S6D) but also altered the relative abundance of specific gut microbes at various taxonomic levels (Fig. S6E and S6F and Fig. 1F). At the genus level, as shown in Fig. 1F and detailed in Table S2, HL0877i increased the relative abundance of beneficial bacterial genera, including Akkermansia, Parabacteroides, and Lachnoclostridium. It reversed alterations caused by ISO-induced injury, characterized by an increase in Alistipes and Clostridium_sensu_stricto_1. In subsequent FMT trials, changes in these five strains were again observed (Table S3), indicating that they may represent characteristic strains associated with disease status.
An FMT experiment was conducted to ascertain the importance of reshaping the gut microbiota through HL0877i in treating HF. Recipient mice were pretreated with an antibiotic cocktail and then orally administered a fecal bacterial suspension from HL0877i-treated donor mice daily (Supporting Information Fig. S7A). After FMT treatment, the EF and FS of recipient mice were significantly enhanced (Fig. S7B), while the serum levels of BNP and inflammatory cytokines, TNF-α and IL-6, were also significantly decreased (Fig. S7C and S7D). Additionally, the extent of myocardial damage, fibrosis, and hypertrophy was alleviated (Fig. S7E–S7H) compared to the model group. These findings indicated that the mice were effectively treated for HF undergoing FMT. Then, fecal samples from the four groups of mice were collected for 16S rDNA sequencing, which confirmed that the recipient and donor groups shared a high degree of similarity (Supporting Information Fig. S8), with no significant differences observed in the Shannon or ACE indices and bacterial composition. Based on these findings, the transplanted gut microbiota appears to have been successfully colonized in the recipient mice, exhibiting an anti-HF effect.
3.　Supplementation of the key metabolite, either HVA or 2OH–VA, ameliorates cardiac hypertrophy to improve HF
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The gut microbiota regulates the synthesis and absorption of microbial metabolites. Consequently, we hypothesized that metabolic changes might underlie the effects of HL0877i on HF. First, significant variations in metabolite profiles were observed by the untargeted metabolomics analysis on fecal samples (Supporting Information Fig. S9A). Focusing on the differential metabolites between the groups, we identified 449 metabolites, of which 364 correspond to HMDB entries, in comparing the model and HL0877i groups. Of these, 63.19% were classified as lipids and lipid-like molecules (Fig. S9B–S9D). We noticed that HL0877i upregulated the levels of 2OH–VA (Fig. S9B), a phenolic acid compound. Furthermore, the volcano plots clearly depicted that the abundances of five metabolites (2OH–VA, gentisic acid, caffeic acid, sinapic acid, and HVA) that belong to phenolic acids and derivatives were significantly upregulated in the HL0877i group (Fig. 1G).
Subsequently, 2OH–VA, which showed the most significant upregulation in abundance (Supporting Information Fig. S10A), and HVA, which demonstrated the most potent protective effect (Fig. S10B), were chosen as representative active metabolites for further investigation. It is noteworthy that, following administration of HL0877i to mice, we observed elevated concentrations of HVA and 2OH–VA in both plasma and cardiac tissue, with HVA levels notably higher than those of 2OH–VA (Supporting Information Fig. S11). HVA and 2OH–VA have displayed promising protective effects against OGD-induced damage and ISO-induced cardiac hypertrophy (Supporting Information Fig. S12). In contrast to HF mice, the oral administration of 30 mg/kg of HVA or 2OH–VA (Fig. 1H) significantly enhanced cardiac function, reduced inflammatory cytokines and BNP levels in serum, and mitigated cardiac damage and fibrosis (Supporting Information Fig. S13A–S13E). WGA staining revealed a significant reduction in cardiac hypertrophy (Fig. 1I and J). Moreover, both HVA and 2OH–VA enhanced the grip strength and endurance capacity of the mice (Fig. S13F and S13G), indicating the potential to improve the prognosis of patients with HF.
4.　 HVA and 2OH–VA suppress the HDAC2–KLF4/INPP5F–AKT–GSK3β signaling pathway to ameliorate pathological hypertrophy
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The metabolites significantly inhibit hypertrophy, a key process in HF pathogenesis, so we further investigated potential signaling pathways to elucidate how these metabolites alleviate hypertrophy. Given that veratric acid, a homolog of HVA and 2OH–VA, has cardiovascular protective effects and is known to modulate the expression of histone deacetylases (HDACs)4. Initially, our findings indicated that the expression of HDAC2 was elevated in cardiomyocytes following OGD injury (Supporting Information Fig. S14A). This upregulation was significantly reduced by treatment with either HVA or 2OH–VA, while the levels of HDAC1 and HDAC3 remained unchanged (Fig. S14B and S14C). The acetylation of histone H3K9, a substrate for HDACs, was upregulated by either HVA or 2OH–VA (Fig. S14D). Similar results were observed in mouse myocardial tissues, where HVA and 2OH–VA increased H3K9 acetylation levels by reducing HDAC2 expression (Fig. 1K–M). Then, we detected the expression of Krüppel-like factor 4 (KLF4) and inositol polyphosphate-5-phosphatase f (INPP5F), which inhibit the transcription and translation of atrial natriuretic peptide (ANP), resulting in antihypertrophic effects5. As depicted in Supporting Information Fig. S15A, the expression of both KLF4 and INPP5F was dramatically downregulated in the hypertrophic myocardium of HF-mice, while ANP expression was upregulated (Fig. 1K). HVA and 2OH–VA could restore the physiological expression levels of these effector proteins. Moreover, INPP5F has been demonstrated to counteract hypertrophy, which leads to the activation of glycogen synthase kinase 3β (GSK3β) through the inactivation of protein kinase B (AKT). As illustrated in Fig. S15B, HVA and 2OH–VA normalized elevated AKT and GSK3β phosphorylation levels in cardiac tissue. Collectively, these findings indicated that HVA and 2OH–VA modulated the HDAC2–KLF4/INPP5F–AKT–GSK3β signaling pathway (Fig. 1N). Additionally, our data demonstrated that mice treated with HL0877i and subjected to FMT also regulate this pathway (Supporting Information Fig. S16), thereby contributing to anti-hypertrophy.
Collectively, our study first reported the therapeutic potential of the Chinese herb Veronica anagallis-aquatica L. in treating HF, and the iridoid glycosides (HL0877i) were the main active ingredients contributing to the anti-HF efficacy. Furthermore, HL0877i can reshape the gut microbiota and elevate the concentrations of the metabolites HVA and 2OH–VA, thereby mitigating cardiac hypertrophy by HDAC2–KLF4/INPP5F–AKT–GSK3β signaling pathway. These findings imply that modulating the gut microbiome to ameliorate cardiac hypertrophy offers innovative strategies for HF treatment, with HL0877i emerging as a promising candidate in gut microbe-dependent therapeutic approaches.
References
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Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res 2022;118:3272—87.
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Su BN, Yang L, Gao K, Jia ZJ. Aquaticol, a bis-sesquiterpene and iridoid glucosides from Veronica anagallis-aquatica. Planta Med 2000;66:281—3.
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Tang WHW, Li DY, Hazen SL. Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol 2019;16:137—54.
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Saravanakumar M, Raja B. Veratric acid, a phenolic acid attenuates blood pressure and oxidative stress in l-NAME induced hypertensive rats. Eur J Pharmacol 2011;671:87—94.
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Yuan YG, Peng WZ, Liu YX, Xu ZS. Palmatine attenuates isoproterenol-induced pathological hypertrophy via selectively inhibiting HDAC2 in rats. Int J Immunopathol Pharmacol 2017;30:406—12.
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Year 2025 volume 15 Issue 6
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Article Info
doi: 10.1016/j.apsb.2025.04.005
  • Receive Date：2024-10-26
  • Online Date：2026-04-03
Article Data
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History
  • Received：2024-10-26
  • Revised：2025-01-30
  • Accepted：2025-02-19
Affiliations
    aState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
    bCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    cYunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from Western Yunnan, Institute of Materia Medica & College of Pharmacy, Dali University, Dali 671000, China
    dKey Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China
    eKey Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, China

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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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