Effect of valsartan on cardiac senescence and apoptosis in a rat model of cardiotoxicity

Abstract

The clinical application of doxorubicin is limited by its cardiotoxicity. The present study investigated the effect of valsartan on doxorubicin-induced cardiotoxicity in rats. Rats were divided into 6 groups: control, control + valsartan (10 mg/kg, for 14 days, orally), doxorubicin-treated (2.5 mg/kg, 3 times/week for 2 weeks, intraperitoneally), valsartan then doxorubicin, valsartan + doxorubicin, and doxorubicin then valsartan. ECG, isolated heart, lipid peroxidation (thiobaribituric acid reactive substances (TBARS)), total antioxidant capacity (TAC), and Bax, Bcl-2, and senescence marker protein 30 (SMP30) gene expression were measured in cardiac tissue. Blood samples were collected to measure lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB). Doxorubicin significantly increased LDH, CK-MB, TBARS, heart rate (HR), Bax gene expression, and -dP/dtmax and decreased TAC, Bcl-2 and SMP30 gene expression, left ventricular developed pressure (LVDP), and +dP/dtmax. Also, doxorubicin lengthened ST, QT, and QTc intervals. Concurrent or post- but not pre-treatment of doxorubicin-treated rats with valsartan reduced LDH, CK-MB, TBARS, HR, Bax gene expression, -dP/dtmax, and ST, QT, and QTc intervals and increased TAC, Bcl-2 and SMP30 gene expression, LVDP, and +dP/dtmax. Therefore, we conclude that concurrent or post- but not pre-treatment of doxorubicin-induced rats with valsartan attenuated doxorubicin-induced cardiotoxicity through inhibiting oxidative stress, apoptosis, and senescence.

Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis

“…Consistent with previous studies [ 39 ], our data showed that DOX administration in rats caused a significant increase in lipid peroxidation, which was manifested by pronounced elevations in MDA and was also accompanied by a notable decrease in TAC of rats’ cardiac tissue. These effects were not unexpected since previous studies had demonstrated DOX-induced depletion of antioxidant molecules including glutathione (GSH) and exhaustion of cardiac antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-P) due to excessive consumption by DOX-generated free radicals [ 40 , 41 ].…”

Advantages of prophylactic versus conventionally scheduled heart failure therapy in an experimental model of doxorubicin-induced cardiomyopathy

“…A number of studies demonstrated detailed histological and electron microscopic data of DOX-induced myocardial changes, such as myofibrillar disarray [60], myofibrillolysis, sarcomeric disintegration [9, 61], contraction band formation [10], and cardiomyocyte hypertrophy [61, 62]. Some of these abnormalities were successfully attenuated by inhibiting the renin–angiotensin–aldosterone system [10, 15, 16]. In contrast with a conventionally scheduled therapy, we demonstrated a well-preserved ultrastructure of the myofilaments when applying a prophylactic treatment, which highlights the importance of the temporal aspects of cardioprotection in preserving myocardial ultrastructure.…”

Protective effects of valsartan administration on doxorubicin‑induced myocardial injury in rats and the role of oxidative stress and NOX2/NOX4 signaling

“…A clinical observational study demonstrated that Val could prevent the acute cardiotoxicity induced by cyclophosphamide, doxorubicin, vincristine and prednisolone, which are standard chemotherapeutic options for treatment of non-Hodgkin lymphoma ( 11 ). More recently, Sakr et al ( 12 ) investigated the effect of Val on DOX-induced cardiotoxicity in rats, and found that concurrent or post-but not pre-treatment with Val attenuated DOX-induced cardiotoxicity by inhibiting oxidative stress, apoptosis and senescence. Another study reported that Val alleviated DOX-induced cardiac dysfunction via regulation of the TGF-β signaling pathway ( 13 ).…”