Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemia-reperfusion injury are mediated through the Akt/Nrf2/HO-1 pathway

Abstract

In clinical practice, the traditional Chinese medicinal herbs, Radix Salvia Miltiorrhiza and Carthamus tinctorius L., are usually prescribed in combination due to their significant cardioprotective effects. However, the mechanisms responsible for these combined effects remain unknown. Thus, in this study, we investigated the mechanisms responsible for the combined effects of Danshensu (DSS) and hydroxysafflor yellow A (HSYA) by establishing a rat model of myocardial ischemia/reperfusion (MI/R), as well as a model of hypoxia/reoxygenation (H/R) using H9c2 cells. The combination index (CI) was calculated using the median-effect method. DSS and HSYA in combination led to a CI value of <1 as regards infarct size in vivo and cell viability in vitro. The rats with MI/R injury that were treated with DSS and/or HSYA were found to have significantly lower levels of creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) and malondialdehyde (MDA), and a lower expressoin of 8-hydroxydeoxyguanosine (8-OHdG), and markedly enhanced superoxide dismutase (SOD) activity. Our in vitro experiments revealed that the cells treated with DSS and/or HSYA had a reduced lactate dehydrogenase (LDH) activity and a decreased percentage of cell apoptosis (increased Bcl-2/Bax ratio, decreased expression of cleaved caspase-3). DSS and HSYA increased the expression of heme oxygenase-1 (HO-1), the phosphorylation of Akt and the trans-location of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, the Akt inhibitor, LY294002, partially hampered the expression of Nrf2 and HO-1. The HO-1 inhibitor, zinc protoporphyrin IX (ZnPP-IX), did not decrease the expression of p-Akt and Nrf2, although it abolished the anti-apoptotic and antioxidant effects of DSS and HSYA. The findings of our study thus demonstrate that DSS and HSYA confer synergistic cardioprotective effects through the Akt/Nrf2/HO-1 signaling pathway, to certain extent, by enhancing the antioxidant defense system and exerting anti-apoptotic effects.

Retracted: Effects of mTOR/NF‐κB signaling pathway and high thoracic epidural anesthesia on myocardial ischemia‐reperfusion injury via autophagy in rats

“…Apoptotic index (AI) referred to the apoptotic degree. AI = apoptotic positive cell number/total cell number × 100% (Hu et al, ).…”

Synergistic antioxidant effects of petunidin and lycopene in H9c2 cells submitted to hydrogen peroxide: Role of Akt/Nrf2 pathway

“…In another part, Hu et al. (2016) found that Danshensu, a main bioactive of Salvia miltiorrhizae , mainly exerted antiapoptotic effects acting on apoptosis‐related proteins, while hydroxysafflor yellow A, the main bioactive of safflower, had more significant effects on antioxidant enzymes. They concluded that the two bioactives acted in a complementary manner that manifested in synergistic antioxidant activity and protective effect against the myocardial ischemia‐reperfusion injury (Hu et al., 2016).…”

“…(2016) found that Danshensu, a main bioactive of Salvia miltiorrhizae , mainly exerted antiapoptotic effects acting on apoptosis‐related proteins, while hydroxysafflor yellow A, the main bioactive of safflower, had more significant effects on antioxidant enzymes. They concluded that the two bioactives acted in a complementary manner that manifested in synergistic antioxidant activity and protective effect against the myocardial ischemia‐reperfusion injury (Hu et al., 2016). Similarly, in the present study, when petunidin and lycopene were mixed at the proper ratio, the synergistic effect was observed, which may be caused by concerted and complementary actions of the two individual compounds, that is, petunidin impacted more on the induction of NQO1 and lycopene on HO‐1, on top of the fact that both compounds upregulated the two enzymes individually.…”

Protective Effect of Hydroxysafflor Yellow A on Nephropathy by Attenuating Oxidative Stress and Inhibiting Apoptosis in Induced Type 2 Diabetes in Rat

“…It has been evidenced [30,31] that HSYA could be protected against kidney injury by its anti-inflammatory action. As an inflammatory mediator, TNF-α has a high correction with the extensive tubular damage in kidney [32,33]; as the previous study suggested, HSYA could inhibit the expression of tumor necrosis factor alpha (TNF-α) [34].…”