Chemotherapy is a kind of common treatment for cancer, but both traditional drugs, such as doxorubicin, cisplatin or paclitaxel, and targeted drugs, like trastuzumab or immune checkpoint inhibitors, can cause a certain degree of cardiotoxicity. Taking doxorubicin as an example, current studies have shown that doxorubicin can cause iron overload in cardiomyocytes, further aggravate oxidative stress [10, 11, 12], at the same time, cardiomyocytes metabolism disorder and structural change are contributed to myocardial cell apoptosis, necrosis and even increasing Gasdermin D sequentially leading to membrane dissolution [13, 14]. However, the specific mechanism of cardiotoxicity caused by targeted drugs has been on studying, but metabolism disorder, oxidative stress and inflammation are potential reasons. Intervening metabolism, reducing oxidative stress and delaying the development of inflammation may benefit the cardiomyocytes damage caused by chemotherapy.
LCZ696 is a new type of anti-heart failure drug, and it also benefits patients with hypertension. Its main components are transformed into LBQ657 and valsartan in vivo, which can inhibit natriuretic peptide system degradation by neprilysin and delay the activation of renin angiotensin aldosterone [15, 16]. From the mechanism, compared with valsartan alone, LCZ696 can significantly improve the active natriuretic peptide, which can be released through ventricular or atrial cardiomyocytes, which activate guanylate cyclase, play a series of positive roles, but the specific biological indicators need to be further verified . In addition, LCZ696, which is clinically known as sacubitril/valsartan, has not been used as a preventive drug for cardiotoxicity caused by chemotherapy. It is necessary to further study its effects on metabolism, oxidative stress and inflammation, so as to clarify its possible effect.
Sirt-family are important regulators of mitochondrial function. Mitochondrial dysfunction plays a key role in cardiovascular diseases, including myocardial hypertrophy, heart failure, pulmonary hypertension, endothelial dysfunction, atherosclerosis, arrhythmia and so on [18, 19, 20]. In our study, the mRNA expression and the content of Sirt3 indicated that the level of metabolism was decreased by trastuzumab. Trastuzumab is a drug that targets a specific receptor common in some breast cancers, and the previous study indicated that knocking down Sirt6 increased the survival of a breast cancer cell exposed to trastuzumab , that is, trastuzumab may have some effect on Sirt-family. However, the pretreatment of LCZ696 in our model ameliorated Sirt3 expression, thus, the myocardial injury caused by trastuzumab was effectively inhibited. In a pressure overload-induced heart failure model, LCZ696 could induced the upregulation of MnSOD through a Sirt3-dependent pathway . We found that, in trastuzumab-induced H9C2 cell model, LCZ696 could increase the mRNA expression of SOD2 and reduce the content of MDA, and then, the fluorescence intensity of ROS was inhibited measured by flow cytometry. In mice with obesity-related metabolic heart disease, LCZ696 could improve myocardial energetics, and neprilysin inhibition exerted a positive effect on diastolic function . Therefore, LCZ696 can improve the level of cell metabolism and downregulated oxidative stress induced by chemotherapeutic drugs.
Pyroptosis, a kind of programmed cell death, was thought to be closely related to inflammation, even pyroptosis was equal to inflammation in some research. In trastuzumab-induced H9C2 cell model, the mRNA and protein expression of NLRP3, ACS, Caspase-1 and IL-1β were significantly increased, but reversed by LCZ696-meaning that targeted chemotherapy was an important factor leading to the aggravation of inflammation and cell death, meanwhile LCZ696 could delay the progress of pyroptosis. A recent study revealed that sacubitril/valsartan (LCZ696) against pathological cardiac remodeling by inhibiting the NLRP3 inflammasome after relief of pressure overload in mice, but it's not pretreatment . Thus, in our study, it also revealed that pretreatment via LCZ696 may reduce NLRP3/ACS inflammasome, substantially further delay myocardial fibrosis and prevent ventricular remodeling.
The therapeutic effect of LCZ696 on heart failure is clear, and some studies have found that LCZ696 can reduce doxorubicin-induced cardiotoxicity identified by Xia et al.  and Boutagy et al.  from a variety of pathways. However, in the field of onco-cardiology, there are few studies of LCZ696 on the prevention of myocardial injury caused by targeted chemotherapy drugs. Therefore, we found that LCZ696 can not only treat heart failure, but also prevent myocardial injury caused by trastuzumab via downregulating ROS and NLRP3-mediated pyroptosis by protecting the activity of Sirt3 in vitro. Next, we will verify whether LCZ696 can protect the heart function of trastuzumab chemotherapy in vivo.