Farrerol Alleviates Myocardial Ischemia/Reperfusion Injury by Targeting Macrophages and NLRP3

Abstract

Myocardial ischemia/reperfusion (I/R) injury is associated with high mortality and morbidity, however, it has no curative treatment. Farrerol (FA), an active compound extracted from rhododendron, has antibacterial, anti-inflammatory, and antioxidant activities, but its effect and mechanism of FA in I/R injury remain unclear. Here, we found that FA alleviated myocardial I/R in vivo, and decreased the secretion of myocardial injury factors (CK-MB, LDH, troponin-1, and NT-proBNP) while inhibiting the release of inflammatory factors (IL-1β, IL-6, and TNF-α). FA could also alleviate excessive oxidative stress by elevating the level of antioxidant enzymes and reducing oxidation products; and decreased reduced the expression of apoptosis-associated proteins (cleaved caspase-3, Bax, and Bcl-2). However, inhibiting the autophagic pathway or knocking out the Nrf2 gene did not eliminate the myocardial protective effect of FA, but interestingly, macrophage clearance and Nlrp3 deficiency effectively blocked the myocardial protective effect of FA. In addition, FA suppressed NLRP3 inflammasome activation by interfering with NLRP3 and NEK7. In conclusion, these results support drug-targeted macrophage therapy for myocardial I/R and indicate that FA may be used as an immunomodulator in clinical therapy for myocardial I/R.

Farrerol prevents Angiotensin II-induced cardiac remodeling in vivo and in vitro

“…These therapeutic effects of Farrerol are mainly due to free radical scavenging, antioxidant and anti-inflammatory properties. Farrerol alleviates myocardial ischemia/Reperfusion injury in vivo ( Zhou et al, 2022 ). We believe that Farrerol plays the same role in cardio-protection from hypertrophy and remodeling.…”

“…The animal experiment was approved by the Animal Research Committee of Dalian Medical University (AEE20029). Farrerol (Selleck, S9552, China) was dissolved in dimethyl sulfoxide (DMSO, Sigma), diluted with DMSO and normal saline, and injected intraperitoneally at a dose of 10 mg/kg/day ( Ma et al, 2021 ; Zhou et al, 2022 ). 2 days after administration, Ang II (1,000 ng/kg/min, 4474-91-3, aladdin) was subcutaneously infused to establish a cardiac remodeling model for 2 weeks via implanted osmotic minipumps (Model 1007D, Alzet, Cupertino, CA, United States).…”

HJ11 decoction restrains development of myocardial ischemia-reperfusion injury in rats by suppressing ACSL4-mediated ferroptosis

“…FTH1 is a critical subunit of ferritin that maintains cellular iron balance to prevent cells from ferroptosis ( Zhao et al, 2021a ). COX2 is a well-known biomarker of ferroptosis onset, and ACSL4 is a sensitive regulator of ferroptosis and a contributor to ferroptosis execution ( Zhao et al, 2021b ; Zhou et al, 2022 ). Interestingly, HJ11 decoction suppresses the expression of COX2 and ACSL4 and enhances the expression of FTH1 and GPX4 in the myocardial tissues of rats with I/R.…”