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Abstract
Doxorubicin (Doxo) is a widely used antineoplastic drug which often induces cardiomyopathy, leading to congestive heart failure through the intramyocardial production of reactive oxygen species (ROS). Icariin (Ica) is a flavonoid isolated from Epimedii Herba (Berberidaceae). Some reports on the pharmacological activity of Ica explained its antioxidant and cardioprotective effects. The aim of our study was to assess the protective activities of Ica against Doxo-detrimental effects on rat heart-tissue derived embryonic cardiac myoblasts (H9c2 cells) and to identify, at least in part, the molecular mechanisms involved. Our results showed that pretreatment of H9c2 cells with 1 μM and 5 μM of Ica, prior to Doxo exposure, resulted in an improvement in cell viability, a reduction in ROS generation, the prevention of mitochondrial dysfunction and mPTP opening. Furthermore, for the first time, we identified one feasible molecular mechanism through which Ica could exerts its cardioprotective effects. Indeed, our data showed a significant reduction in Caveolin-1(Cav-1) expression levels and a specific inhibitory effect on phosphodiesterase 5 (PDE5a) activity, improving mitochondrial function compared to Doxo-treated cells. Besides, Ica significantly prevented apoptotic cell death and downregulated the main pro-autophagic marker Beclin-1 and LC3 lipidation rate, restoring physiological levels of activation of the protective autophagic process. These results suggest that Ica might have beneficial cardioprotective effects in attenuating cardiotoxicity in patients requiring anthracycline chemotherapy through the inhibition of oxidative stress and, in particular, through the modulation of Cav-1 expression levels and the involvement of PDE5a activity, thereby leading to cardiac cell survival.
Highlights
According to the World Health Organization, cardiovascular diseases (CVDs) account for about one third of all global deaths
We showed a PDE5a inhibitory activity of Ica 1 μM which becomes statistically significant at 5 μM when compared to the positive control and to the known PDE5a inhibitor sildenafil
In light of this result, we further investigated the modulation of PDE5a activity in the Doxo cardiotoxicity pattern, highlighting the possible protective effect exerted by Ica through direct inhibition of PDE5a
Summary
According to the World Health Organization, cardiovascular diseases (CVDs) account for about one third of all global deaths. Cancer- related heart diseases are serious and dramatic health problems. The antineoplastic therapy administered to improve cancer patient survival often leads to the onset of CVDs [1]. CVDs, such as heart failure (HF) and myocardial dysfunction, account for about half of the deaths of cancer patients [2,3]. Among the antineoplastic drugs capable of inducing severe late side effects, anthracyclines are a well-known example [4]. Doxorubicin (Doxo), known as Adriamicyn, is an anthracycline isolated from the bacterium Streptomyces peucetius var. Caesius, and is the hydroxylated congener of daunorubicin [5] Doxorubicin (Doxo), known as Adriamicyn, is an anthracycline isolated from the bacterium Streptomyces peucetius var. caesius, and is the hydroxylated congener of daunorubicin [5]
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