Icariin Protects H9c2 Rat Cardiomyoblasts from Doxorubicin-Induced Cardiotoxicity: Role of Caveolin-1 Upregulation and Enhanced Autophagic Response

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.

Icariin synergizes therapeutic effect of dexamethasone on adriamycin-induced nephrotic syndrome

“…Our study confirmed that ICA could enhance DEX-induced podocyte autophagy and reduce the dose of hormone drugs. Similarly, in studies in which rat cardiomyocytes fight doxorubicin-induced cardiotoxicity, ICA has been shown to promote the lipidation rate of autophagy markers beclin-1 and LC3 and restore the physiological activation levels of protective autophagy [30]. This suggests that our study is consistent with the study of Scicchitano et al [30], which lays the foundation for the mechanism by which ICA treats nephrotic syndrome and other diseases.…”

Palmitate-Induced Cardiac Lipotoxicity Is Relieved by the Redox-Active Motif of SELENOT through Improving Mitochondrial Function and Regulating Metabolic State

“…For the detection of intracellular ROS, H9c2 cells (100,000 per well) were seeded on coverslips in 6-well plates and exposed to PA and PSELT, alone or in co-treatment for 24 h. At the end of the experimental protocol, H9c2 cardiomyocytes were incubated with 10 μmol/L CM-H 2 DCFDA at 37 °C for 30 min in the dark, and then the cells were carefully rinsed with DPBS and visualized under a fluorescence microscope (Olympus; 20× objective) [ 28 , 29 ]. For measuring the production of total ROS by flow cytometry, H9c2 cells were treated as above, collected, washed with DPBS, and stained with H2DCFDA.…”

Advances in Nano-formulated Polyphenols for Protection against Cardiovascular diseases

“…However, the gastrointestinal concentration of EGCG especially in the jejunum was significantly increased after nanoparticle administration which is considered a major site for flavonoid absorption. 101 Icariin is another flavonoid known to exhibit cardio protection against ischemic heart disease, 102 cardiotoxicity, 103 and atherosclerosis 104 but limited by its poor pharmacokinetics. 105 Icariin was formulated as a nanodrug incorporated into monomethyl ether PEG (mPEG).…”