LCZ696 ameliorates doxorubicin-induced cardiomyocyte toxicity in rats

Abstract

Doxorubicin (DOX)-based chemotherapy induces cardiotoxicity, which is considered the main bottleneck for its clinical application. In this study, we investigated the potential benefit of LCZ696, an angiotensin receptor–neprilysin inhibitor against DOX-induced cardiotoxicity in rats and H9c2 cells and determined whether the mechanism underlying any such effects involves its antioxidant activity. Male Sprague–Dawley rats were randomly separated into four groups, each consisting of 15 rats (DOX (1.5 mg/kg/day intraperitoneally for 10 days followed by non-treatment for 8 days); DOX + valsartan (31 mg/kg/day by gavage from day 1 to day 18); DOX + LCZ696 (68 mg/kg/day by gavage from day 1 to day 18); and control (saline intraperitoneally for 10 days). DOX-induced elevation of cardiac troponin T levels on day 18 was significantly reduced by LCZ696, but not valsartan. The DOX-induced increase in myocardial reactive oxygen species (ROS) levels determined using dihydroethidium was significantly ameliorated by LCZ696, but not valsartan, and was accompanied by the suppression of DOX-induced increase in p47phox. LCZ696 recovered the DOX-induced decrease in phosphorylation of adenosine monophosphate-activated protein kinase and increased the ratio of Bax and Bcl-2. In H9c2 cardiomyocytes, LCZ696 reduced DOX-induced mitochondrial ROS generation and improved cell viability more than valsartan. Our findings indicated that LCZ696 ameliorated DOX-induced cardiotoxicity in rat hearts in vivo and in vitro, possibly by mediating a decrease in oxidative stress.

Utilization of Quince (Cydonia oblonga) Peel and Exploration of Its Metabolite Profiling and Cardioprotective Potential Against Doxorubicin-Induced Cardiotoxicity in Wistar Rats

“…However, in pretreated groups, the Hw/Bw ratio did not differ considerably in contrast to the control DOX group, except for the standard simvastatin group that showed a substantial variance ( p < 0.01) in contrast to the DOX group. The Hw/Bw ratio was found to decrease in our study, which is ascribed to the loss of myofibrilla and degradation of the myocardial tissue triggered by the cardiotoxic effect of DOX. , …”

“…The Hw/Bw ratio was found to decrease in our study, which is ascribed to the loss of myofibrilla and degradation of the myocardial tissue triggered by the cardiotoxic effect of DOX. 38 , 39 …”

LCZ696 Ameliorates Isoproterenol-Induced Acute Heart Failure in Rats by Activating the Nrf2 Signaling Pathway

“…These results suggest that the regulation of the endogenous antioxidant defense system by LCZ696 is important in protecting rats from HF-induced myocardial injury. Isoproterenol is widely used to treat heart failure in mice [33]. In the case of chronic heart disease, the SD rats can be pretreated with isoprenaline followed by treating with LCZ6969.…”

Role of Oxidative Stress and Inflammation in Doxorubicin-Induced Cardiotoxicity: A Brief Account

“…It has been shown that upon Doxo treatment mitochondrial fission protein 1 (Mtfp1), a GTPase also known as Mtp18 widely involved in mitochondrial fission, is upregulated [25]. Furthermore, it has been proved that Doxo affects mitochondrial fission by enhancing the phosphorylation of the dynamin-related protein 1 (DRP1), which is a GTPase responsible for outer mitochondrial membrane scission [26][27][28]. Mitochondrial fusion, in contrast, is inhibited, since Mitofusin 1 and 2 (MFN 1/2), that are GTPases related to mitochondrial fusion, are downregulated during Doxo treatment [29].…”