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Statins Inhibit Toll-Like Receptor-4: a Potential Role for Attenuating Doxorubicin-Induced Cardiomyopathy
The anthracycline doxorubicin (Dox) is widely used as an effective antitumor drug. Cardiotoxicity leading to congestive heart failure is the primary factor limiting the clinical use of Dox. Cardiac inflammation and generation of oxidative stress are known to contribute to Dox-induced cardiomyopathy. Cytokine release mediated by activation of the innate immune system is believed to be involved in the pathogenesis of Dox-induced cardiotoxicity. The innate immune system has long been regarded as the first line of defense against foreign pathogens. Toll-like receptors (TLRs) are a part of the innate immune system and are germline-encoded receptors involved in the cardiac stress reaction. They are key compo-nents of the innate immunity and are activated in response to pathogens as well as non-pathogenic components of dam-aged tissues. Among the TLR family, TLR4 is the most extensively studied in the pathogenesis of cardiomyopathy. TLR4 activation not only triggers an inflammatory response but also results in extracellular matrix degradation and causes a vicious cycle of which the outcome is cardiomyopathy. On the other hand, TLR4 deficiency improves left ven-tricular function and attenuates key pathophysiological mechanisms in Dox-induced cardiomyopathy. Consequently, any substance that blocks the TLR4 receptor or disrupts its signaling may provide protection against cardiomyopathy in Dox-treated patients. Statins are currently-marketed reductase inhibitors that are used to reduce levels of LDL; they also have other beneficial effects including decrease of oxidative stress and vascular inflammation. More recently, statins have been shown to inhibit the TLR4-mediated inflammatory response in individuals with a specific TLR4 genotype. It is pos-sible that these agents could be used off-label to diminish the likelihood of doxorubicin cardiotoxicity, permitting higher doxorubicin doses. We propose the hypothesis that statins can prevent doxorubicin-induced cardiomyopathy.
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