Background: Cardiac hypertrophy is characterized by an enlarged heart muscle, often due to increased workload or chronic heart diseases. Postn protein (periostin) plays a significant role in cardiac hypertrophy by influencing cardiomyocyte proliferation, inflammatory response, and fibrosis. The TGF-β and NF-κB pathways exacerbate inflammatory responses and structural changes in the heart during cardiac hypertrophy. Chlorogenic acid, found in plants, has antioxidant and anti-inflammatory properties, making it a potential candidate for inhibiting cardiac hypertrophy. Method: We used angiotensin II-induced H9c2 cardiomyocytes to construct a cell model of cardiac hypertrophy. Cells were categorized into control, model, shPostn, chlorogenic acid, and shPostn+chlorogenic acid groups. Various parameters, including cell surface area, activity, apoptosis rate, and expression levels of Postn, TGF-β/NF-κB pathway-related proteins, and mRNA, were evaluated. Results: Compared to the control group, the model group exhibited increased cell surface area and apoptosis rate, along with decreased cell activity. However, intervention with shPostn or chlorogenic acid led to significant reductions in cell surface area and apoptosis rate, coupled with increased cell viability. The shPostn+chlorogenic acid group showed further improvements. In addition, protein and mRNA expressions related to Postn, TGF-β/NF-κB pathways, and cardiac hypertrophy markers were upregulated in the model group but downregulated in the intervention groups, particularly the shPostn+chlorogenic acid group. Conclusion: Chlorogenic acid exerts its inhibitory effect on cardiac hypertrophy by modulating the TGF-β/NF-κB pathway through Postn protein. This study sheds light on potential therapeutic strategies for mitigating cardiac hypertrophy induced by angiotensin II and highlights chlorogenic acid as a promising candidate for further exploration in treating this condition.

Cardiac hypertrophy, characterized by an enlarged heart muscle, is a critical pathological condition often resulting from increased cardiac workload or chronic heart diseases.1–3 It is associated with adverse outcomes, such as heart failure and sudden cardiac death, making it a significant health concern. Understanding the molecular mechanisms driving cardiac hypertrophy is crucial for developing effective therapeutic strategies.

Postn protein (periostin) is an extracellular matrix protein encoded by the gene POSTN, which plays an important role in cardiac hypertrophy.4 During cardiac hypertrophy, the expression level of Postn protein increases.5 It participates in crucial biological processes, such as cardiomyocyte proliferation, inflammatory response, fibrosis, and myocardial remodeling.6 Postn protein’s involvement in cardiac hypertrophy is evident in its ability to interact with other extracellular matrix proteins, promoting the proliferation and differentiation of cardiomyocytes and contributing to cardiac hypertrophy.7 

The TGF-β and NF-κB pathways are also key players in cardiac hypertrophy.8 These pathways interact with TGF-β pathway activation inducing NF-κB activation, and vice versa.9 This interaction exacerbates the inflammatory response and fibrosis, contributing to adverse structural changes in the heart during cardiac hypertrophy. Understanding and intervening in the TGF-β/NF-κB pathway is crucial for managing cardiac hypertrophy effectively.10 

Chlorogenic acid, found in various plants such as coffee beans, apples, and tea leaves, has garnered attention for its potential role in inhibiting cardiac hypertrophy.11 It exhibits antioxidant properties, neutralizing free radicals and reducing oxidative stress damage.12 In addition, its anti-inflammatory effects inhibit the release of inflammatory mediators, offering therapeutic potential for alleviating inflammatory diseases.13 Chlorogenic acid’s multifaceted biological activities make it a promising candidate for inhibiting cardiac hypertrophy. Cardiac hypertrophy is a complex condition influenced by various molecular pathways, including the Postn protein, TGF-β/NF-κB pathway, and compounds such as chlorogenic acid. Investigating these mechanisms is crucial for developing targeted interventions to mitigate cardiac hypertrophy and its associated complications.

The study aims to investigate whether chlorogenic acid (CGA) can mitigate cardiac hypertrophy by modulating the expression of Postn protein and regulating the TGF-β/NF-κB signaling pathway. The hypothesis posits that CGA’s antioxidant and anti-inflammatory properties may attenuate cardiac hypertrophy. Specific objectives include evaluating the impact of CGA on cardiac hypertrophy parameters, such as heart size, cardiomyocyte proliferation, and fibrosis; elucidating its modulation of Postn protein expression through molecular techniques; exploring the involvement of the TGF-β/NF-κB pathway in CGA-mediated effects; and assessing CGA’s therapeutic potential in improving cardiac function and preventing adverse outcomes. Overall, this study aims to contribute insights into CGA’s role as a potential therapeutic agent for cardiac hypertrophy and associated cardiovascular conditions.

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki and received approval from the institutional ethics committee. Informed consent was obtained from all participants involved in the study, and measures were taken to ensure confidentiality and privacy of sensitive information throughout the research process.

The materials used in this study included the rat cardiomyocyte cell line H9c2 (ATCC), fetal bovine serum, DMEM (HyClone Company), Postn, α3, α5, β3, β5, TGF-β, NF-κB, ANP, BNP, and β-MHC monoclonal antibodies (Wuhan Sanying), chlorogenic acid, Ang II (Shanghai Sikejie), Goat Anti-Rabbit Secondary Antibody (Shanghai Beyuntian), CCK-8 Cell Detection Kit (Shanghai Beyuntian), shPostn (Shanghai Gemma Biological Co., Ltd.), primers (Shanghai Sangon Biology), Apoptosis Detection Kit (Sizhengbai Biotechnology), ELISA Kit (Hangzhou Lianke Biotechnology), inverted microscope (Zeiss), flow cytometer (Beckman Coulter, USA), and gel imaging analysis system (Bio-Rad, USA).

To construct the cardiomyocyte hypertrophy model, H9c2 cardiomyocytes were trypsinized and cultured in a complete medium. After synchronization, cells were induced with 1 µmol/l Ang II for 48 h. The experimental groups included the control group (DMEM complete medium), model group (no special treatment), shPostn group (transfected with shPostn lentivirus), chlorogenic acid group (treated with 100 µmol/l chlorogenic acid), and shPostn+chlorogenic acid group (treated with 100 µmol/l chlorogenic acid + shPostn lentivirus). The concentrations of chlorogenic acid and the duration of Ang II exposure were chosen based on previous studies and established protocols.

Measurement of cell surface area

Cells were cultured in 24-well plates, imaged under a Nikon inverted microscope, and analyzed using Image-ProPlus software. Ten cells were selected from five randomly chosen fields of view to calculate the mean cell surface area.

CCK-8 detection of cell viability

Cells were treated with CCK-8 solution, and the absorbance at 450 nm wavelength (OD450) was measured using a microplate reader after 1.5 h of incubation. Cell viability was calculated as the percentage relative to the control group.

Western blot analysis

Total cell protein was extracted using RIPA lysate, and protein concentration was measured using the BCA method. Target proteins (Postn, α3, α5, β3, β5, TGF-β, NF-κB, ANP, BNP, and β-MHC) were separated by SDS-PAGE, transferred to a membrane, and incubated with primary antibodies overnight at 4 °C. After washing and incubation with HRP-labeled secondary antibodies, protein expression was quantified using a gel imaging analysis system with GAPDH as an internal reference.

RT-PCR detection of mRNA expression

Total cellular RNA was extracted using TRIzol, and cDNA was synthesized. Real-time PCR was performed using specific primers, and mRNA expression levels were quantified using the 2-ΔΔCt method relative to GAPDH.

Flow cytometry

Cells were washed with pre-cooled PBS, stained with AnnexinV/FITC and PI solutions, and analyzed by flow cytometry to detect the apoptosis rate in each group.

Statistical analysis

The data were analyzed using the SPSS 26.0 software. One-way ANOVA and LSD t-test were used for comparisons among multiple groups and pairwise comparisons, respectively. A significance level of P < 0.05 was considered statistically significant.

Compared to the control group, the cell surface area significantly increased in the model group (p < 0.05). However, both the shPostnRNA group and the chlorogenic acid group exhibited significantly reduced cell surface areas compared to the model group (p < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group showed a further reduction in cell surface area compared to the shPostn and chlorogenic acid groups (p < 0.05), and no significant difference was observed compared to the control group (P > 0.05) (Fig. 1).

FIG. 1.

Comparison of cell surface area among different experimental groups. The cell surface area was significantly increased in the model group compared to the control group (p < 0.05). Both the shPostnRNA group and the chlorogenic acid group showed significantly reduced cell surface areas compared to the model group (p < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited a further reduction in cell surface area compared to the shPostn and chlorogenic acid groups (p < 0.05), with no significant difference compared to the control group (P > 0.05).

FIG. 1.

Comparison of cell surface area among different experimental groups. The cell surface area was significantly increased in the model group compared to the control group (p < 0.05). Both the shPostnRNA group and the chlorogenic acid group showed significantly reduced cell surface areas compared to the model group (p < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited a further reduction in cell surface area compared to the shPostn and chlorogenic acid groups (p < 0.05), with no significant difference compared to the control group (P > 0.05).

Close modal

Regarding cell activity, the model group showed a significant decrease compared to the control group (P < 0.05). In contrast, both the shPostn and chlorogenic acid groups exhibited significantly increased cell activity compared to the model group (P < 0.05), with no significant difference between these two groups. The shPostn+chlorogenic acid group showed a further increase in cell activity compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05) (Fig. 2).

FIG. 2.

Comparison of cell activity among different experimental groups. Cell activity significantly decreased in the model group compared to the control group (P < 0.05). Both the shPostn and chlorogenic acid groups exhibited significantly increased cell activity compared to the model group (P < 0.05), with no significant difference between these two groups. The shPostn+chlorogenic acid group showed a further increase in cell activity compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

FIG. 2.

Comparison of cell activity among different experimental groups. Cell activity significantly decreased in the model group compared to the control group (P < 0.05). Both the shPostn and chlorogenic acid groups exhibited significantly increased cell activity compared to the model group (P < 0.05), with no significant difference between these two groups. The shPostn+chlorogenic acid group showed a further increase in cell activity compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

Close modal

Protein expressions of Postn, α3, α5, β3, β5, NF-κB, TGF-β1, ANP, BNP, and β-MHC were significantly upregulated in the model group compared to the control group (P < 0.05). However, both the shPostn and chlorogenic acid groups exhibited significant downregulation of these proteins compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group showed further downregulation compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05) (Fig. 3).

FIG. 3.

Comparison of protein expressions among different experimental groups. The protein expressions of Postn, α3, α5, β3, β5, NF-κB, TGF-β1, ANP, BNP, and β-MHC were significantly upregulated in the model group compared to the control group (P < 0.05). Both the shPostn and chlorogenic acid groups exhibited significant downregulation of these proteins compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group showed further downregulation compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

FIG. 3.

Comparison of protein expressions among different experimental groups. The protein expressions of Postn, α3, α5, β3, β5, NF-κB, TGF-β1, ANP, BNP, and β-MHC were significantly upregulated in the model group compared to the control group (P < 0.05). Both the shPostn and chlorogenic acid groups exhibited significant downregulation of these proteins compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group showed further downregulation compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

Close modal

The relative mRNA expressions of Postn, α3, α5, β3, β5, NF-κB, and TGF-β1 were significantly upregulated in the model group compared to the control group (P < 0.05). However, both the shPostn and chlorogenic acid groups showed significant downregulation compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited further downregulation compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05) (Fig. 4).

FIG. 4.

Comparison of mRNA expressions among different experimental groups. The relative mRNA expressions of Postn, α3, α5, β3, β5, NF-κB, and TGF-β1 were significantly upregulated in the model group compared to the control group (P < 0.05). Both the shPostn and chlorogenic acid groups showed significant downregulation of these mRNA expressions compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited further downregulation compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

FIG. 4.

Comparison of mRNA expressions among different experimental groups. The relative mRNA expressions of Postn, α3, α5, β3, β5, NF-κB, and TGF-β1 were significantly upregulated in the model group compared to the control group (P < 0.05). Both the shPostn and chlorogenic acid groups showed significant downregulation of these mRNA expressions compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited further downregulation compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

Close modal

In addition, the apoptosis rate significantly increased in the model group compared to the control group (P < 0.05). However, both the Postn-siRNA group and the chlorogenic acid group showed a significant decrease in the apoptosis rate compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited a further reduction in the apoptosis rate compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05) (Fig. 5).

FIG. 5.

Comparison of apoptosis rates among different experimental groups. The apoptosis rate significantly increased in the model group compared to the control group (P < 0.05). Both the Postn-siRNA group and the chlorogenic acid group showed a significant decrease in the apoptosis rate compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited a further reduction in the apoptosis rate compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

FIG. 5.

Comparison of apoptosis rates among different experimental groups. The apoptosis rate significantly increased in the model group compared to the control group (P < 0.05). Both the Postn-siRNA group and the chlorogenic acid group showed a significant decrease in the apoptosis rate compared to the model group (P < 0.05), with no significant difference between these two groups (P > 0.05). The shPostn+chlorogenic acid group exhibited a further reduction in the apoptosis rate compared to the shPostn and chlorogenic acid groups (P < 0.05), with no significant difference compared to the control group (P > 0.05).

Close modal

Further analysis revealed a positive correlation between the expressions of TGF-β, NF-κB, and β-MHC with the expression of Postn, indicating Postn’s pivotal role in myocardial hypertrophy and its regulation of downstream molecules (Fig. 6).

FIG. 6.

Correlation analysis between the expression of TGF-β, NF-κB, and β-MHC with the expression of Postn. The results demonstrate a positive correlation, indicating Postn’s significant role in myocardial hypertrophy and its positive regulation of downstream molecules.

FIG. 6.

Correlation analysis between the expression of TGF-β, NF-κB, and β-MHC with the expression of Postn. The results demonstrate a positive correlation, indicating Postn’s significant role in myocardial hypertrophy and its positive regulation of downstream molecules.

Close modal

This study provides valuable insights into the complex mechanisms underlying cardiac hypertrophy and the potential therapeutic role of chlorogenic acid in mitigating its progression. Cardiac hypertrophy involves intricate cellular and molecular changes influenced by various signaling pathways, including the renin–angiotensin–aldosterone system (RAAS) and TGF-β/NF-κB pathways.14,15 The findings of this study align with the existing literature, demonstrating that interventions targeting these pathways can attenuate hypertrophic responses.16,17 Specifically, the results indicate that chlorogenic acid effectively reduces cardiomyocyte surface area and apoptosis rate and enhances cell viability, potentially through the modulation of Postn protein and subsequent downstream signaling cascades.

Chlorogenic acid’s ability to regulate Postn protein and attenuate the TGF-β/NF-κB pathway represents a novel therapeutic avenue in cardiac hypertrophy management.18–21 Previous studies have highlighted chlorogenic acid’s anti-inflammatory and antioxidant properties, which may contribute to its cardioprotective effects.22,23 By inhibiting the TGF-β/NF-κB pathway, chlorogenic acid likely mitigates inflammation-induced myocardial remodeling and fibrosis, thus preserving cardiac function.24,25 Moreover, the study’s findings suggest a direct correlation between Postn protein expression and hypertrophic responses, further elucidating the intricate molecular mechanisms underlying cardiac hypertrophy.

However, the study has several limitations that warrant consideration. The use of H9c2 cardiomyocytes as a model system may not fully recapitulate the complexities of cardiac physiology observed in vivo. Future studies employing primary cardiomyocytes or animal models are essential to validate these findings and better understand chlorogenic acid’s therapeutic potential. In addition, while the study elucidates chlorogenic acid’s effects on the TGF-β/NF-κB pathway, further mechanistic investigations are necessary to delineate the precise molecular interactions involved.26 

This study sheds light on the promising therapeutic effects of chlorogenic acid in attenuating cardiac hypertrophy through the regulation of Postn protein and the TGF-β/NF-κB pathway. By integrating these findings with the existing literature, we gain a deeper understanding of the molecular mechanisms underlying cardiac hypertrophy and identify novel targets for therapeutic intervention. Future research efforts should focus on validating these findings in vivo and elucidating the detailed molecular mechanisms to advance the development of effective treatments for cardiac hypertrophy.

This study was supported by Science and Technology Planning Project of Jiangxi Provincial Health Commission “Study on the anti-ocular uveal melanoma effect of bendazole and its new drug delivery dosage form based on tubulin target” (No. SKJP220210301), Young Leading Talent Project of Science and Technology Bureau of Fuzhou City, Jiangxi Province, “Study on the anti-ocular uveal melanoma effect of bendazole and its new drug delivery dosage form based on tubulin target” (Project No. 2021ED009), and Fuzhou Science and Technology Planning Project of Jiangxi Province “Study on the effect of tubulin targeted mebendazole on breast cancer” (No. 109025488028).

The authors have no conflicts to disclose.

Ethics approval for experiments reported in the submitted manuscript on animal or human subjects was granted. This study was approved by the Medical ethics committee of The First Hospital of Jilin University.

Naiwei Li: Conceptualization (equal); Data curation (equal); Formal analysis (equal); Funding acquisition (equal); Methodology (equal); Project administration (equal); Writing – original draft (equal); Writing – review & editing (equal). Zhou Yan: Resources (equal); Validation (equal). Fang Wang: Investigation (equal); Validation (equal). Mustafa Sawsan Aloahd: Conceptualization (equal); Formal analysis (equal); Funding acquisition (equal); Writing – review & editing (equal). Lui Na: Conceptualization (equal); Methodology (equal); Software (equal).

Data Is available with the corresponding author on reasonable request.

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