Triptolide Attenuates Myocardial Ischemia/Reperfusion Injuries in Rats by Inducing the Activation of Nrf2/HO-1 Defense Pathway

Abstract

Triptolide is a bioactive component of Chinese herbal plant Tripterygium wilfordii Hook F that has recently been noted to attenuate hepatic and cerebral ischemia/reperfusion (I/R) injuries in rodents. To investigate whether triptolide could protect against myocardial I/R injuries, triptolide (25, 50 or 100 μg/kg) was administrated in Wistar rats that underwent left anterior descending coronary artery ligation in this study. Our data showed that triptolide pretreatment could attenuate myocardial infarction, increase the fractional shortening and left ventricular systolic pressure and decrease the left ventricular end-diastolic pressure in ischemic rats. Also, triptolide was noted to inhibit the activities of lactate dehydrogenase and creatine kinase in I/R rats. Moreover, triptolide administration suppressed macrophage infiltration, inhibited the overproduction of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and malondialdehyde (MDA) in reperfused myocardium tissues and upregulated the activities of antioxidative superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GPx). In addition, nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the activity of its downstream target Heme oxygenase-1 (HO-1) in ischemic myocardium tissues were enhanced by triptolide pretreatment. In addition, the HO-1 inhibitor, zinc protoporphyrin-IX, abrograted the cardiac protection mediated by triptolide. Our study reveals a novel cardioprotective effect of triptolide in rats with I/R injuries, wherein the activation of Nrf2/HO-1 signaling was involved.

The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches

“…Azafrin, a natural carotenoid, have shown to induce Nrf2 downstream target genes such as HO-1, GCLC, GCLM, Trx1 and GST ( Yang et al, 2018a ). This is in consistent with another study showing that pre-treatment with triptolide, a diterpenoid epoxide protected Wistar rat from myocardial ischemia/reperfusion injuries by suppressing the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and inducing Nrf2-regulated antioxidant enzymes (SOD, GSH, GPx, and HO-1) ( Yu et al, 2016 ). Besides, coffee constituent 5- O -caffeoylquinic acid (CGA) has also been shown to enhance Nrf2 nuclear translocation and increase the transcriptional expression of γ-GCL, HO-1 and GSTA1 ( Boettler et al, 2011 ).…”

MicroRNA-140-5p aggravates hypertension and oxidative stress of atherosclerosis via targeting Nrf2 and Sirt2

“…In the process of body defense, Nrf2 serves a critical function in the oxidative stress induced by exogenous toxicants. Keap1 is one of the major receptors of Nrf2; all of its cysteine residues are able to interact with the HO-1 inducer (5). This inducer interacts with specific residues on Keap1 and causes conformational changes in Keap1, which are able to trigger Nrf2 dissociation from Keap1 (21).…”

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor of the antioxidant stress pathway (5). Under normal physiological conditions, Nrf2 is stably bound to Kelch-like enoyl-CoA hydratase-associated protein 1 (Keap1) and is stabilized in the cytoplasm by Keap1 (5). The bound Nrf2 cannot translocate into the nucleus, and neither is it able to exert its unique transcriptional activity (6).…”

“…Under stress, Keap1 can be decoupled from Nrf2, and unbound Nrf2 is then translocated into the nucleus and bind to the antioxidant element heme oxygenase 1 (HO-1) (6). This process, to a certain extent, enhances the gene expression of its downstream enzymes (5). Among them, the most typical include ubiquitin, phase II detoxification enzymes, antioxidant proteins and proteasomes, expression of which further increases the ability of cells to resist oxidative stress (7).…”

MicroRNAs as crucial mediators in the pharmacological activities of triptolide (Review)

“…Triptolide exhibits profound immunosuppressive activity by regulating the proportion of immune cells and inhibiting the release of immune factors (7). Triptolide also alleviates renal and myocardial pathological injuries, and exerts protective roles in kidney and cardiovascular diseases (8,9). However, despite its desirable clinical applications, treatment with triptolide is…”