Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction

Abstract

Background: Doxorubicin (DOX) is an effective broad-spectrum antitumor drug, but its clinical application is limited due to the side effects of cardiac damage. Astragaloside IV (AS-IV) is a significant active component of Astragalus membranaceus that exerts cardioprotective effects through various pathways. However, whether AS-IV exerts protective effects against DOX-induced myocardial injury by regulating the pyroptosis is still unknown and is investigated in this study. Methods: The myocardial injury model was constructed by intraperitoneal injection of DOX, and AS-IV was administered via oral gavage to explore its specific protective mechanism. Cardiac function and cardiac injury indicators, including lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and brain natriuretic peptide (BNP), and histopathology of the cardiomyocytes were assessed 4 weeks post DOX challenge. Serum levels of IL-1β, IL-18, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) and the expression of pyroptosis and signaling proteins were also determined. Results: Cardiac dysfunction was observed after the DOX challenge, as evidenced by reduced ejection fraction, increased myocardial fibrosis, and increased BNP, LDH, cTnI, and CK-MB levels (p < 0.05, N = 3-10). AS-IV attenuated DOX-induced myocardial injury. The mitochondrial morphology and structure were also significantly damaged after DOX treatment, and these changes were restored after AS-IV treatment. DOX induced an increase in the serum levels of IL-1β, IL-18, SOD, MDA and GSH as well as an increase in the expression of pyroptosis-related proteins (p < 0.05, N = 3-6). Besides, AS-IV depressed myocardial inflammatory-related pyroptosis via activation of the expressions of nuclear factor E2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) (p < 0.05, N = 3). Conclusions: Our results showed that AS-IV had a significant protective effect against DOX-induced myocardial injury, which may be associated with the activation of Nrf-2/HO-1 to inhibit pyroptosis.

LncRNA GAS5 restrains ISO-induced cardiac fibrosis by modulating mir-217 regulation of SIRT1

“…And it has been shown that GAS5 is involved in renal tubular cell pyroptosis 33 , ovarian cancer 34 and diabetic cardiomyopathy (DCM) 35 induced by NLRP3 inflammasome activation. Previous studies have shown that pyroptosis activation is associated with Cardiac Dysfunction 36 . In the current study, we tested the expression of NLRP3, Caspase-1, IL-1β and GSDMD which are pyroptosis markers.…”

The role of the inflammasome and pyroptosis in heart failure

“…28 While the occurrence of inflammasome-mediated pyroptosis has been observed in various tissues and cell types, additional evidence is necessary to establish its definitive role in the progression and underlying mechanisms of certain heart diseases. 29 Epidemiological studies have highlighted obesity, hypertension, and aging as key risk factors for HF, thus intensifying research efforts to investigate the crucial pathological involvement of inflammasome and pyroptosis in the pathogenesis of HF. 30 Pyroptosis, a novel form of programmed cell death, has garnered attention in recent years due to its close association with the progression of inflammasome-related heart failure (HF).…”

Redox Regulation of Microglial Inflammatory Response: Fine Control of NLRP3 Inflammasome through Nrf2 and NOX4

“…The main link between Nrf2 and NLRP3 are intracellular ROS, that could come from both mitochondrial ROS and NOX activation, and can activate both proteins; however, its actions are opposite. In fact, it has been demonstrated that Nrf2 activation before NLRP3 inflammasome activation reduces inflammation in various in vitro and in vivo models of central and peripheral inflammation [ 33 , 34 , 35 , 36 ]. Consistent with all these studies, we have shown that 24 h treatment with tBHQ prior to NLRP3 inflammasome activation reduces NLRP3 inflammasome components both in WT and NOX4 KO mice ( Figure 4 ).…”