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Selective Activation of Cannabinoid Receptor 2 Attenuates Myocardial Infarction via Suppressing NLRP3 Inflammasome

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Abstract

The administration of cannabinoid receptor 2 (CB2R) agonist has been reported to produce a cardioprotective effect against the pathogenesis and progression of myocardial infarction (MI). Here in this study, we investigated the specific mechanism related to inflammatory suppression. JWH-133 was used for the activation of CB2R. MI mice models and cardiomyocytes under oxygen-glucose deprivation (OGD) challenge were used for the in vivo and in vitro studies, respectively. Detection of cardiac infarct size and levels of myocardial enzymes as well as echocardiographic examination were applied to assess MI severity and cardiac function. Cell viability and lactate dehydrogenase (LDH) release were detected in vitro. Real-time-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the levels of proinflammatory cytokines. Western blot was used for the analysis of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. We found that the administration of CB2R agonist attenuated the severity of MI through reducing infarct size ratio and levels of myocardial enzymes and improved cardiac function in ejection fraction (EF), fractional shortening (FS), left ventricular end-systolic diameter (LVESD), and left ventricular end-diastolic diameter (LVEDD) in MI mice. JWH-133 also produced a cardioprotective effect in murine primary cardiomyocytes by improving cell viability and LDH release. JWH-133 largely reduced the production and secretion of proinflammatory cytokines, which was significantly attenuated by AM630. HU308 showed the same effects as JWH-133. Taken together, we demonstrated for the first time the cardioprotective effect of CB2R agonist and its NLRP3 inflammasome-related mechanism in MI.

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Funding

This work was supported by a Zhejiang Provincial Medicine Health Science and Technology Program (No. 2014KYB013).

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Authors and Affiliations

  1. Geriatric Department, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, 158 Shangtang Road, Zhejiang, Hangzhou, China

    Wen Yu

  2. Department of Emergency, the Second Affiliated Hospital of Zhejiang Chinese Medical University, 318 Chaowang Road, Zhejiang, Hangzhou, China

    Guangjun Jin & Jiancheng Zhang

  3. Department of Cardiology, Zhejiang Hospital, 12 Lingyin Road, Zhejiang, Hangzhou, China

    Wei Wei

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Supplemental Fig. 1

HU308 suppresses the serum level of proinflammatory cytokines, while AM630 attenuated the effects of JWH-133. MI mice models were created through occlusion of left anterior descending coronary artery. (a) Mice were intraperitoneally injected with HU308 at 5 min before ischemia. Quantitative analysis of proinflammatory cytokines including IL-1β, IL-18, IFN-γ and TNF-α in serum at 6-h post-MI (n = 6). **P < 0.01 vs. sham group; ##P < 0.01 vs. MI group without HU308; data are presented as mean ± SEM. (b) Mice were intraperitoneally injected with JWH-133 (10 mg/kg) at 10 min before ischemia followed by intraperitoneal administration of AM630 at 5 min before ischemia. Quantitative analysis of proinflammatory cytokines including IL-1β, IL-18, IFN-γ and TNF-α in serum at 6-h post-MI (n = 6). **P < 0.01 vs. sham group; #P < 0.05 vs. MI group; ##P < 0.01 vs. MI group; $$P < 0.01 vs. MI + JWH-133 group; data are presented as mean ± SEM. (TIF 42498 kb)

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Yu, W., Jin, G., Zhang, J. et al. Selective Activation of Cannabinoid Receptor 2 Attenuates Myocardial Infarction via Suppressing NLRP3 Inflammasome. Inflammation 42, 904–914 (2019). https://doi.org/10.1007/s10753-018-0945-x

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