Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone

Ya-han Liu1,2, Yan Liu1,2, Xu Zhang1,2, Li Fang1,2, Bei-lei Zhao1,2, Nan-ping Wang3
1 Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
2 Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
3 East China Normal University Health Science Center, Shanghai 200241, China
Correspondence to: Nan-ping Wang:,
DOI: 10.1038/s41401-022-00858-x
Received: 15 August 2021
Accepted: 3 January 2022
Advance online: 21 February 2022


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.
Keywords: peroxisome proliferator-activated receptor-γ; endocannabinoids; cardiac hypertrophy; mammalian target of rapamycin

Article Options

Download Citation

Cited times in Scopus