Abstract
Inflammation and apoptosis are main pathological processes that lead to the development of cardiac hypertrophy. Lupeol, a natural triterpenoid, has shown anti-inflammatory and anti-apoptotic activities as well as potential protective effects on cardiovascular diseases. In this study we investigated whether lupeol attenuated cardiac hypertrophy and fibrosis induced by pressure overload in vivo and in vitro, and explored the underlying mechanisms. Cardiac hypertrophy was induced in mice by transverse aortic constriction (TAC) surgery, and in neonatal rat cardiomyocytes (NRCMs) by stimulation with phenylephrine (PE) in vitro. We showed that administration of lupeol (50 mg ·kg-1· d-1, i.g., for 4 weeks) prevented the morphological changes and cardiac dysfunction and remodeling in TAC mice, and treatment with lupeol (50 μg/mL) significantly attenuated the hypertrophy of PE-stimulated NRCMs, and blunted the upregulated hypertrophic markers ANP, BNP, and β-MHC. Furthermore, lupeol treatment attenuated the apoptotic and inflammatory responses in the heart tissue. We revealed that lupeol attenuated the inflammatory responses including the reduction of inflammatory cytokines and inhibition of NF-κB p65 nuclear translocation, which was mediated by the TLR4-PI3K-Akt signaling. Administration of a PI3K/Akt agonist 740 Y-P reversed the protective effects of lupeol in TAC mice as well as in PE-stimulated NRCMs. Moreover, pre-treatment with a TLR4 agonist RS 09 abolished the protective effects of lupeol and restored the inhibition of PI3K-Akt-NF-κB signaling by lupeol in PE-stimulated NRCMs. Collectively, our results demonstrate that the lupeol protects against cardiac hypertrophy via anti-inflammatory mechanisms, which results from inhibiting the TLR4-PI3K-Akt-NF-κB signaling.
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Acknowledgements
This study was supported by the Key Project from the National Natural Science Foundation (82000229), National Key R&D Program of China (2018YFC1311300), Development Center for Medical Science and Technology National Health and Family Planning Commission of the People’s Republic of China (The prevention and control project of the cardiovascular disease, 2016ZX-008-01), and Science and Technology Planning Projects of Wuhan (2018061005132295).
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DL, MX, and QZT designed research; DL, YYG, XFC, HLQ, SC, XFZ, and QZ performed the experiments; DL and YYG analyzed data; DL and MX wrote the paper.
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Li, D., Guo, Yy., Cen, Xf. et al. Lupeol protects against cardiac hypertrophy via TLR4-PI3K-Akt-NF-κB pathways. Acta Pharmacol Sin 43, 1989–2002 (2022). https://doi.org/10.1038/s41401-021-00820-3
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DOI: https://doi.org/10.1038/s41401-021-00820-3
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