Effect of Vitamin D Supplementation on Doxorubicin-Induced Cardiotoxicity in Rats

Abstract

Abstract Background Doxorubicin-induced cardiotoxicity is a worldwide problem. Vitamin D is a well-known beneficial vitamin for bone growth and calcium homeostasis but recently it is also known for its cardioprotective effects. The aim of this study is to investigate the potential protective role of vitamin D on the cardiac dysfunction induced by chronic doxorubicin exposure, and to throw more light on the possible underlying mechanism (s) for such effect. Materials and Methods: 70 female Albino-rats were divided into 4 groups; control group (C), Doxorubicin-treated group (Dox): given i.p. injection of Dox in a dose of 2.5 mg/kg body weight (cumulative dose: 15 mg/kg) over 3 weeks, vitamin Dsupplemented group (Vit D): given vitamin D by oral gavage in a dose of 500 IU/kg daily, 5 days a week, also for 3 weeks and the combined Doxorubicintreated+vitamin D-supplemented group (Dox+Vit D). At the end of the experiment, ECG was recorded and in vitro isolated heart study was performed on Langendoroff preparation to measure peak tension (PT), time to peak tension (TPT), half relaxation time (HRT) and myocardial flow rate (MFR). Body and cardiac weights, plasma levels of brain naturetic peptide (BNP), cardiac troponin I (cTnI), vitamin D and total calcium and cardiac tissue heat shock protein 20, total antioxidant capacity (TAC) and malondialdehyde (MDA) were measured. Also, cardiac tissues were histopathologically assessed. Results: Dox-treated rats showed significant decrease in the final body weight (fBW), significant prolongation of the P-R interval, QRS duration, observed Q-T (Q-TO) and corrected Q-T (Q-Tc) with significant depression of the R voltage. In addition, there was a significant decrease in the in vitro heart rate, significant depression in PT, PT/LV and MFR together with significant prolongation in TPT& 3 HRT. These changes were accompanied by significant elevation of plasma BNP, cTnI and in cardiac tissue MDA and a significant decrease in plasma vit D, total calcium and cardiac tissue TAC and HSP20. Histopathological examination revealed markedly distorted muscle fibers with indistinct cell borders, bright eosinophilic cytoplasm, intra-cytoplasmic vacuoles and small pyknotic nuclei or absent nuclei, together with interstitial edema & aggregates of inflammatory cells and thick irregular collagen fibers in between the muscle fibers. Concomitant supplementation of vitamin D to the doxorubicin treated rats resulted in significant decrease in PR interval, QRS duration, MDA and significant increase PT, PT/LV, MFR, MFR/LV, plasma vitamin D, total calcium and TAC compared to the Dox treated rats to be insignificantly different from the control group. Plasma BNP and cTnI were significantly decreased while cardiac HSP20 was significantly increased compared to the Dox-treated rats, yet these parameters were still significant from the control group. Meanwhile, fBW, Q-TO and Q-Tc intervals, and TPT remained insignificantly changed from the DOX group. These findings were associated by regaining the normal collagen fiber distribution between cardiac muscle fibers with resolution of interstitial edema. Conclusion: Vitamin D supplementation can partially mitigate cardiac dysfunction induced by chronic doxorubicin by improving the cardiac antioxidant state and heat shock protein 20 level. Key words: Doxorubicin, cardiac dysfunction, vitamin D, isolated heart studies, BNP, HSP20.