Abstract
Rosiglitazone (RSG) is a synthetic agonist of peroxisome proliferator-activated receptor-γ (PPARγ), which plays a central role in the regulation of metabolism. Meta-analyses have suggested that RSG is associated with increased cardiovascular risk. However, the mechanisms underlying such adverse cardiac effects are still poorly understood. Here, we found that activation of PPARγ by RSG stimulated the endocannabinoid system (ECS), a membrane lipid signaling system, which induced cardiac hypertrophy. In neonatal rat cardiomyocytes, RSG increased the level of anandamide (AEA); upregulated the expression of N-acyl phosphatidylethanolamine phospholipase D (NapePLD), a key enzyme for AEA synthesis; and downregulated the expression of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of AEA. Importantly, PPARγ activation increased the expression of cannabinoid receptor type 1 (CB1) through an identified binding site for PPARγ in the CB1 promoter region. Moreover, both the in vitro and in vivo results showed that inhibition of the ECS by rimonabant, an antagonist of CB1, attenuated RSG-induced cardiac hypertrophy, as indicated by decreased expression of cardiac hypertrophy markers (ANP and BNP), deactivation of the mTOR pathway, and decreased cardiomyocyte size. Thus, these results demonstrated that the ECS functions as a novel target of PPARγ and that the AEA/CB1/mTOR axis mediates RSG-induced cardiac remodeling.
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Acknowledgements
This study was supported by grants from the National Key R&D Program of China [2018YFA0800600] and National Science Foundation of China [81830015, 82170422 and 81670408].
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NPW and YHL conceived the study and designed the experiments. YHL, YL, XZ, and BLZ performed the experiments. LF helped perform analysis. NPW, YHL, and YL wrote the manuscript.
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Liu, Yh., Liu, Y., Zhang, X. et al. Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone. Acta Pharmacol Sin 43, 2302–2312 (2022). https://doi.org/10.1038/s41401-022-00858-x
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DOI: https://doi.org/10.1038/s41401-022-00858-x
