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Published on: March 29, 2024
Catalpol Alleviates HFpEF via Inhibition of the S100A8-RAGE-NOX4 Inflammatory Axis in Murine Hearts
1Department of Geriatrics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
Insights
Catalpol (CAT) effectively treats heart failure with preserved ejection fraction (HFpEF) by reducing inflammation and fibrosis. It works by targeting the S100A8/RAGE/NOX4 pathway, offering a potential new therapy for HFpEF.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Heart failure with preserved ejection fraction (HFpEF) presents significant therapeutic challenges.
- Understanding the molecular mechanisms underlying HFpEF is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the therapeutic potential of catalpol (CAT) in a mouse model of HFpEF.
- To elucidate the underlying molecular mechanisms of CAT's action in HFpEF.
Main Methods:
- Established an HFpEF mouse model using a high-fat diet and L-NAME, followed by CAT treatment.
- Assessed cardiac function via echocardiography and cardiac tissue pathology.
- Utilized network pharmacology, transcriptomics, and in vitro cell models (H9C2 cells) to identify and validate CAT's targets and pathways.
- Employed Western blotting and qPCR to confirm signaling pathway modulation.
Main Results:
- CAT significantly improved cardiac function and reduced myocardial inflammation and fibrosis in HFpEF mice.
- Network pharmacology and transcriptomic analyses identified the RAGE signaling pathway as a key target of CAT.
- CAT downregulated the S100A8/RAGE/NOX4 axis and its downstream effector MMP2.
- In vitro studies confirmed CAT's ability to alleviate Ang II-induced cardiomyocyte hypertrophy and reduce inflammatory markers.
Conclusions:
- Catalpol demonstrates significant cardioprotective effects in HFpEF.
- CAT exerts its beneficial effects by suppressing myocardial inflammation and fibrosis via the S100A8/RAGE/NOX4 signaling axis.
Purpose:
This study aimed to elucidate the therapeutic effects of catalpol (CAT) on heart failure with preserved ejection fraction (HFpEF) and explore its underlying mechanisms.
Methods:
An HFpEF mouse model was established by combining a high-fat diet with N^ω^-nitro-L-arginine methyl ester administration, followed by CAT treatment for four weeks. Cardiac function was assessed by echocardiography, while histopathological changes were evaluated using hematoxylin-eosin and Masson's trichrome staining. Network pharmacology and transcriptomic analyses were integrated to identify the core targets and signaling pathways of CAT in HFpEF. In vitro, H9C2 were stimulated with angiotensin II (Ang II), followed by CAT treatment, with recombinant rat S100A8 used to specifically activate the TLR4/RAGE pathway. Western blotting (WB) and quantitative real-time PCR were performed to validate the predicted signaling mechanisms both in vivo and in vitro.
Results:
In vivo, CAT markedly improved multiple pathological and functional abnormalities in HFpEF mice, including obesity, glucose intolerance, hypertension, diastolic dysfunction, myocardial inflammation, and fibrosis. Integrated network pharmacology and transcriptomic analyses consistently identified the RAGE signaling pathway as the key pathway of CAT. Molecular docking revealed strong binding affinities between CAT and S100A8, RAGE, NOX4, ERK1, and MMP2. WB results further demonstrated that CAT significantly downregulated the S100A8/RAGE/NOX4 axis and its downstream effector MMP2 in cardiac tissue. In vitro, CAT alleviated Ang II-induced cardiomyocyte hypertrophy, reduced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and the heart failure marker ANP, and inhibited S100A8, RAGE, and NOX4 protein levels. Notably, recombinant S100A8 activation weakened the protective effects of CAT.
Conclusion:
CAT exerts cardioprotective effects against HFpEF by suppressing myocardial inflammation and fibrosis through modulation of the S100A8/RAGE/NOX4 signaling axis and its downstream effectors.
