MSCs enhances the protective effects of valsartan on attenuating the doxorubicin-induced myocardial injury via AngII/NOX/ROS/MAPK signaling pathway

Abstract

Objective: To verify if AngII/NOX/ROS/MAPK signaling pathway is involved in Doxorubicin (DOX)-induced myocardial injury and if mesenchymal stem cells (MSCs) could enhance the protective effects of valsartan (Val) on attenuating DOX-induced injury in vitro . Methods: Reactive oxygen species (ROS) formation and the protein expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling were assessed in H9c2 cardiomyocytes exposed to DOX for 24 h in the absence or presence of Val, NADPH oxidase inhibitor DPI or knockdown and overexpression of NADPH oxidase subunit: NOX2 and NOX4, co-culture with MSCs, respectively. Finally, MTT assay was used to determine the cell viability of H9c2 cells, MDA-MB-231 breast cancer cells and A549 pulmonary cancer cells under Val, DOX and Val+ DOX treatments. Results: DOX increased ROS formation and upregulated proteins expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling including p-p38, p-JNK, p-ERK in H9c2 cells. These effects could be attenuated by Val, DPI, NOX2 siRNA and NOX4 siRNA. Meanwhile, overexpression of NOX2 and NOX4 could significantly increase DOX-induced ROS formation and further upregulate apoptotic protein expressions and protein expressions of MAPK signaling. MSCs on top of Val further enhanced the protective effects of Val on reducing the DOX-induced ROS formation and downregulating the expression of apoptotic proteins and MAPK signaling as compared with Val alone in DOX-treated H9c2 cells. Simultaneous Val and DOX treatment did not affect cell viability of DOX-treated MDA-MB-231 breast cancer cells or A549 pulmonary cancer cells but significantly improved cell viability of DOX-treated H9c2 cardiomyocytes. Conclusions: AT 1 R/NOX/ROS/MAPK signaling pathway is involved in DOX-induced cardiotoxicity. Val treatment significantly attenuated DOX-induced cardiotoxicity, without affecting the anti-tumor effect of DOX. MSCs enhance the protective effects of Val on reducing the DOX-induced toxicity in H9c2 cells.

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNK/P38 MAPK pathway in a rat model

“…Moreover, AT1R blockade by valsartan downregulated JNK/p38-MAPK through inhibition of AT1R-mediated NADPH oxidase and ROS formation. These findings correspond with previous study demonstrated that valsartan corrected AT1R-induced NOX/ROS/MAPK pathway leading to the prevention of cardiomyocyte hypertrophy ( Cheng et al, 2021 ). To our knowledge, there is no prospective study showed the link between the cardiotoxicity of gefitinib and RAS system.…”

Ellagic acid protects against angiotensin II‐induced hypertrophic responses through ROS‐mediated MAPK pathway in H9c2 cells

“…This finding demonstrates that MAPK signaling pathways is involved in Ang II‐mediated hypertrophic events 59 . The previous studies have also reported that inhibition of NOX activity by an antioxidant led to a significant decrease in the phosphorylation levels of ERK1/2 and p38 in the in vitro study, suggesting that NOX‐mediated ROS production plays a critical role in the activation of MAPK signaling pathways and the development of cardiac injury 11 . In this present study, we found that EA mitigates Ang‐II‐elevated ROS production, thereby inhibiting MAPK activation.…”

“…Immoderate production of ROS is believed to be the possible mechanism causing cardiac fibrosis, hypertrophy, apoptosis, and cardiac remodeling in cardiomyocytes induced by Ang-II. 11 Previous studies have shown that activating Ang-II/AT-R1 pathways induces the expression of NOX-derived ROS. Production of ROS stimulates the phosphorylation of p38 and the mitogen-activated protein kinase (MAPK) signaling pathway, leading to myocardial hypertrophy.…”

“…This hormone is crucial in causing hypertension and can also stimulate heart hypertrophy and heart failure. Immoderate production of ROS is believed to be the possible mechanism causing cardiac fibrosis, hypertrophy, apoptosis, and cardiac remodeling in cardiomyocytes induced by Ang‐II 11 . Previous studies have shown that activating Ang‐II/AT‐R1 pathways induces the expression of NOX‐derived ROS.…”

Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy

“…In addition, Dox activates the motility-related protein 1 (Drp1) by enhancing the expression of NOX1 and NOX4, further inducing mitochondrial division, and causing the NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes [86]. It was found that knockdown of NOX2 and NOX4 can prevent excessive generation of ROS and attenuated DIC [87,88].…”