Abstract
Resveratrol shows promizing anti-inflammatory effects in recent clinical trials, however its function in cardiovascular patients remains conflicting, suggesting there may be new mechanisms underlying its cardioprotective activity. Acute sympathetic stress induces early activation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome in cardiomyocytes as a critical step for triggering cardiac inflammation. Thus, this study explored targets of resveratrol activity involved in the inhibition of early inflammasome activation in cardiomyocytes following acute sympathetic stress. Network pharmacology was used to analyze common candidate targets in the sympathetic stress pathway, resveratrol activity, and myocardial inflammation and showed the Phosphoinositol 3—kinase (PI3K)/serine threonine protein kinase (Akt) signaling pathway and the target AKT1 may play a critical role. Molecular docking provided support for potential binding of resveratrol on AKT1. Furthermore, the effect of resveratrol on AKT1 activation was determined in cardiomyocytes. resveratrol dose-dependently inhibited AKT1 activation after activation of β-adrenoceptor. The AKT1 inhibitor A-674563 suppressed the activation of the NLRP3 inflammasome in cardiomyocytes following β-adrenoceptor activation, suggesting that AKT1 is a critical regulator molecule upstream of the NLRP3 inflammasome. Consistently, treatment with resveratrol suppressed β-adrenoceptor-mediated NLRP3 inflammasome activation in both cardiomyocytes and mouse hearts, as well as the resultant cardiac inflammation. In conclusion, resveratrol targets AKT1 to inhibit NLRP3 inflammasome activation in cardiomyocytes and cardiac inflammation following acute sympathetic stress. AKT1 is an important target of resveratrol, which should be considered as a treatment option for cardiovascular patients, especially those at risk of acute sympathetic stress.
Highlights
Inflammation plays a critical role in the progression of various cardiovascular diseases and anti-inflammatory strategies have been shown to have promising therapeutic potential
The present study found that AKT1 phosphorylation is the upstream mechanism that promotes activation of the NLRP3 inflammasome in cardiomyocytes after isoproterenol treatment
Resveratrol can target AKT1 to inhibit its phosphorylation by isoproterenol treatment, resulting in suppression of inflammasome activation in cardiomyocytes and cardiac inflammation (Figure 7)
Summary
Inflammation plays a critical role in the progression of various cardiovascular diseases and anti-inflammatory strategies have been shown to have promising therapeutic potential. The results of clinical trials on the cardiac protective effect of resveratrol remain conflicting (Dyck et al, 2019), which suggests its role in the heart may involve new unidentified targets and may be dependent on specific pathologic conditions. Acute sympathetic stress has been reported to induce cardiac inflammation by activating the pyrin domain containing 3 (NLRP3) inflammasome It plays a critical role in immune cells, the inflammasome is early activated in cardiomyocytes following acute sympathetic stress, which triggers cardiac inflammation. (Xiao et al, 2018; Cao et al, 2021) It remains unknown whether and how resveratrol inhibits the early inflammasome activation in cardiomyocytes following acute sympathetic stress
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