clinical application of doxorubicin (doX) is hampered by its potential cardiotoxicity, however angiotensin receptor blockers could attenuate doX-induced cardiomyopathy. The present study tested the hypothesis that simultaneous administration of valsartan (Val) with doX could prevent doX-induced myocardial injury by modulating myocardial nad(P)H oxidase (noX) expression in rats. eight-week-old male Sprague-dawley rats were randomly divided into control (con), doX, and doX+Val groups. after 10 weeks, surviving rats underwent echocardiography examination, myocardial mrna and protein expression detection of noX1, noX2 and noX4. H9c2 cells were used to perform in vitro experiments, reactive oxygen species (roS) production and apoptosis were observed under the conditions of down-or upregulation of noX2 and noX4 in doX-and DOX+Val-treated H9C2 cells. Cardiac function was significantly improved, pathological lesion and collagen volume fraction were significantly reduced in the DOX+Val group compared with the doX group (all P<0.05). Myocardial protein and mRNA expression of NOX2 and NOX4 was significantly downregulated in doX+Val group compared with in the doX group (all P<0.05). In vitro, roS production and apoptosis in doX-treated H9c2 cells was significantly reduced by noX2-small interfering (si)rna and noX4-sirna, and significantly increased by overexpressing NOX2 and NOX4. To conclude, Val applied simultaneously with doX could prevent doX-induced myocardial injury and reduce oxidative stress by downregulating the myocardial expression of noX2 and noX4 in rats.

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.

This study aimed to compare the prevalence of hypertension between the island and rural residents in Dalian, China, and to explore associated risk factors of hypertension in order to provide evidence for the establishment of targeted strategy of hypertension prevention and treatment for island and rural residents. The modified MONICA questionnaire survey was performed on 7764 island and rural residents aged ≥40 years (including 2652 island residents and 5112 rural residents). Our data showed that totally weighted prevalence of hypertension was significantly higher in rural residents than in island residents (61.9% vs. 55.2%, P<0.001). Multivariate binary logistic regression analysis showed that older age, higher BMI, lower education level, and higher LDL-C and UA levels were independently associated with increased risk of having hypertension both in island and in rural residents. The weighted awareness rate (29.9% vs. 17.3%, P<0.001), treatment rate (51.4% vs. 28.5%, P<0.001), and control rate (36.3% vs. 24.0%, P=0.001) of hypertension were all significantly higher in island residents than those in rural residents. In conclusion, our survey shows that the epidemics of hypertension are extremely high in surveyed residents in island and rural areas of Dalian city, while awareness, treatment, and control rats of hypertension in these residents are much lower than the national level. The scenario is even worse in rural residents as compared with island residents of Dalian, China.

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