MF, mainly caused by the death of ischemic cells in the process of myocardial infarction that leads to a reparative response in which the damaged tissue is replaced with a fibrotic scar, can lead to impairment of cardiac function and finally causes adverse outcomes of heart failure [30]. However, there is no therapeutic strategy that can ensure its reversal at present [31]. Evidences have shown that TPL has the characteristics of anti-inflammatory and antitumor [9]. This study found that TPL could inhibit the activation of NLRP3 inflammasome and improve MF by inhibiting NF-κB pathway.
This study found that TPL could inhibit the activation of NLRP3 inflammasome and improve MF by inhibiting NF-κB pathway.
TPL has been shown to have potent antitumor activity in various preclinical cancer models [8], such as lung cancer, breast cancer and pancreatic cancer [32–34]. However, the effect of TPL on MF was still unclear. MF can contribute to cardiac dysfunction in many pathophysiologic conditions [12]. The levels of LVED, LVES, LVEF and LVFS are main indexes of cardiac function [35]. This study showed that TPL improved cardiac dysfunction in MF rats. LVED, LVES, LVIDs and LVPWs were significantly upregulated, while LVEF and LVFS were significantly decreased in MF rats, indicating that the systolic and diastolic functions of rat hearts were significantly impaired; and the cardiac dysfunction of MF rats was effectively improved by TPL treatment. The concentrations of ANP and BNP are closely associated with cardiac function [21]. The levels of ANP and BNP in MF rats were significantly higher, while the levels of ANP and BNP in TPL group were significantly decreased. Consistently, it has been revealed that TPL therapy improves cardiac function through upregulation of MAPK signaling transduction [36]. In brief, TPL could effectively improve cardiac dysfunction in MF rats.
MF can cause myocardial tissue disorder and collagen deposition [22]. The collagen fibers in the rats of MF and DMSO groups were abundant. The collagen volume fraction of rats in MF and DMSO groups was increased significantly, and TPL group reduced CVF of rats significantly. The tissue injury in MF rats was upregulated significantly while that in TPL group was decreased effectively, indicating that TPL could improve pathological damage of MF rats. TPL inhibits collagen gel and suppresses the production of fibronectin [37]. A study has shown can alleviation effect of TPL on the diabetic renal fibrosis by inhibiting miR-141-3p/PTEN/Akt/mTOR pathway [38]. This study explored the role of TPL in alleviating the fibrosis and the expression of fibrosis-related factors. The fibrosis related factors (TGF-β1, COL1 and COL3) expressions in MF and DMSO groups were much higher, while those in TPL group were much lower. Consistently, TPL inhibits airway smooth muscle cells malignant behaviors induced by TGF-β1 significantly [39]. These suggested that TPL could alleviate MF and downregulate the fibrosis related factors expression in MF rats.
Cardiac dysfunction is often accompanied by inflammation [24]. Our results showed that the levels of inflammatory factors (IL-1β, IL-18 and TNF-α) in MF and DMSO groups were upregulated significantly, while TPL treatment decreased the expression of inflammatory factors effectively. It is reported that TPL can downregulate the expressions of IL-1β and TNF-α [40]. TPL attenuates inflammatory responses in endothelial cells [41]. In brief, these results suggested that TPL could downregulate the level of inflammatory in MF rats.NLRP3 inflammasome can finally produce a mature form of highly inflammatory cytokines [42]. The mRNA and protein levels of NLRP3 and ASC were increased significantly in MF and DMSO groups, while TPL treatment decreased their levels effectively. It is reported that TPL can inhibit the activation of NLRP3 inflammasome and protect against the inflammatory injury in diabetic kidney disease [15]. We speculate that TPL may improve MF by regulating NLRP3 inflammasome pathway. To test our hypothesis, we added NLRP3 inflammasome activator Nigericin in TPL group. Our results demonstrated that mRNA expressions of inflammatory factors and fibrosis related factors in TPL + Nigericin group were higher. There is a previous study supporting that TPL protects against pressure overload of hearts by inhibiting the activation of NLRP3 inflammasome [43]. Treatment with TPL exerts the anti-inflammatory effects by downregulating NLRP3 inflammasome in nephritis [44]. In brief, it was suggested that TPL improved MF by inhibiting the activation of NLRP3 inflammasome pathway.
NF-κB pathway is reported to play an essential role in myocardial inflammation as a transcription factor [29]. TPL improves podocyte apoptosis and proteinuria by inhibiting NF-κB/GADD45B pathway [45]. We deduced that TPL might inhibit NLRP3 inflammasome via inhibiting NF-κB pathway. The results showed that P65 phosphorylation levels in MF and DMSO groups were elevated, while TPL treatment downregulated the levels effectively. Next, we treated the TPL group with NF-κB pathway activator Jaceosidin. The levels of inflammatory factor and fibrosis factors in TPL + Jaceosidin group were significantly enhanced. TPL may suppress inflammatory response of endothelial cells by inhibiting activation of NF-κB [41]. There is little research on the effect of TPL on inhibiting MF via NF-κB pathway. Our study confirmed that TPL could improve MF by inhibiting NF-κB pathway and the activation of NLRP3 inflammasome.
In summary, this study supported that TPL could inhibit the activation of NLRP3 inflammasome by inhibiting NF-κB pathway, thus improving MF. Whether there is a deeper regulatory mechanism between TPL and NF-κB pathway in MF remains to be further studied. Our results showed that TPL was only a preventive method and does not necessarily reverse the MF established after ISO injection. Its therapeutic effect needs to be further studied. Studies have shown that TPL can inhibit inflammation [46, 41]. There may be some feasibility in the TPL treatment. However, TPL is also the main toxic component, which has serious side effects on many important tissues. The kidney is very vulnerable to the side effects of TPL as an important excretory organ, which greatly limits the clinical application of TPL [47]. Therefore, the research on the toxicity reduction and efficiency enhancement of TPL is of great practical significance and needs to be further explored.It is the future research trend to transfer the mechanism of TPL on improving MF to clinical application.