DOXO is a powerful anthracycline widely used as an anticancer drug in the clinic, but it is known to induce cardiotoxicity . Most of the DOXO-induced cardiotoxicity can be attributed to the formation of reactive oxygen species (ROS) . Moreover, it has been reported that DOXO produces oxygen free radicals, which cause damage in proteins and DNA by lipid peroxidation as well as interference with the cytoskeleton structure [4,22]. In addition, it has been reported that DOXO causes oxidative stress and depletes antioxidants, which might damage the myocardial cell membrane, making it more permeable and ruptured .
In the current study, the H&E and semithin sections of the DOXO group (group II) showed degenerated and fragmented cardiac muscle fibers with disrupted transverse striations and a significant decrease in the mean cardiomyocyte diameter as compared with all the groups. Some investigators [16,24] have reported results similar to those of the current study. Congested blood vessels were observed with inflammatory cellular infiltration and extravasated red blood cells in between the degenerated cardiac muscle fibers in the present study. These findings are in agreement with those of some authors , who have reported marked granular blood cells between the degenerated cardiac muscle fibers.
The previous changes were confirmed by an electron microscopic examination, which showed cardiac muscle fiber nuclei with an irregular nuclear membrane. Areas of degenerated myofibrils and irregularly arranged mitochondria with a dense matrix were observed. Widening of the intercalated discs was also observed. These results have been reported by some authors, who reported that this myofibrillar injury might be a secondary event after mitochondrial dysfunction, which could lead to imbalance in calcium uptake and loss of ATP production. These factors are known to be important in normal myofibrillar function [25,26]. The collagen fiber content was significantly increased in the DOXO group (group II) compared with group I, a finding that has been reported by other authors .
Examination of sections of group III (GSE+DOXO) of the current work showed preservation of the normal pattern of cardiac muscle fibers almost similar to that of group I, but with some inflammatory cellular infiltration between the cardiac muscle fibers, and some muscle fibers appeared to have disrupted striations. Some authors  have reported similar results and attributed this protective effect to scavenging of free radicals formed by DOXO.
Proanthocyanidins have been shown to exert a novel range of biological, pharmacological, therapeutic, and chemoprotective properties against oxygen free radicals and oxidative stress [6,8,28]. Grape seed proanthocyanidin extract attenuated exogenous H2O2 and oxidant stress, improving cell survival and allowing the recovery of contractile function in cultured cardiomyocytes. Its protective effects were because of its ability to scavenge ROS directly and possibly chelate iron and copper involved in the generation of ROS .
In addition to its antioxidant properties, procyanidin has been shown to modulate the activity of antioxidant enzymes such as cyclooxygenase and lipoxygenase to limit the production of free radicals [29,30]. Moreover, grape seeds could prevent DNA fragmentation and inhibit apoptotic signaling pathways . The improvement in cardiac myofibrils observed on electron microscopic examination in this study was in agreement with the observations of some authors . The collagen fibers showed a significant decrease compared with group II in the current study. This result is in agreement with other works .
It is noteworthy that some authors have reported that procyanidin (GSE) did not attenuate the antitumor activity of DOXO, whereas treatment with procyanidin induced cytotoxicity in the carcinoma cells. This suggests that it may have antitumor activity . The potential cytotoxicity of procyanidins to tumor cells makes it more promising to examine its use as an adjunct in DOXO chemotherapy .
In the present study, H&E and semithin sections of group IV (telmisartan+DOXO) showed almost normal cardiac muscle fibers compared with the control group. Meanwhile, congested blood vessels were observed between the cardiac muscle fibers. The cardioprotective effect of telmisartan could be attributed to the marked suppression of inflammation, endoplasmic reticulum stress, and myocardial apoptosis [32,33]. Moreover, some investigators  have reported that DOXO-induced cardiotoxicity is associated with a marked increase in malondialdehyde, which is a marker of lipid peroxidation and an indicator of oxidative injury. These elevated levels of malondialdehyde were significantly decreased in the heart tissue of DOXO-treated rats that were also treated with telmisartan, which suggested that it protected the myocardium against DOXO-induced lipid peroxidation. In addition, some authors  have suggested that the activity of GPx, which is an important enzyme that protects against oxidative stress, was also decreased in DOXO-treated rats, and the combination of DOXO with telmisartan counteracted the depletion of this enzyme. Group IV showed a significant decrease in collagen fibers compared with group II in this study. This result was in agreement with the work of other investigators .
DOXO affected the structure of the rat's heart, which can be protected by GSE and telmisartan. However, the protective effects of GSE on DOXO-induced cardiac injury should be studied for a longer duration of time to obtain more definitive results. In addition, natural antioxidant food such as GSE is safer than chemically prepared drugs such as telmisartan. So we recommend further study with different time schedule (long period) of GSE as it is a well-known natural antioxidant food.
There are no conflicts of interest.
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