Abstract
Doxorubicin (Dox) is known to cause heart failure in some cancer patients. Despite extensive studies over the past half century, the subcellular basis of Dox-induced cardiomyopathy (DIC) is still elusive. Earlier, we suggested that Dox causes a delayed activation of unfolded protein response (UPR) which may promote mitochondrial Bax activity leading to cardiomyocyte death. As a follow up, using NO donor, S-Nitroso-N-acetyl-d,l-penicillamine (SNAP), and/or NOS inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), we now show that endoplasmic reticulum (ER) stress promotes inflammation through iNOS/NO-induced TLR2 activation. In vivo Dox treatment increased mitochondrial iNOS to promote ER stress as there was an increase in Bip (Grp78) response, proapoptotic CHOP (DDIT3) and ER-mediated Caspase 12 activation. Increased iNOS activity is associated with an increase in TLR2 and TNF-α receptor associated factor 2 (TRAF2). These two together with NF-κB p105/50 expression and a synergistic support through ER stress, promote inflammatory response in the myocardium leading to cell death and ultimately fostering DIC conditions. In the presence of NOS inhibitor, such detrimental effects of Dox were inhibited, suggesting iNOS/NO as key mediators of Dox-induced inflammatory as well as apoptotic responses.
Highlights
Irreversible and life-threatening cardiotoxicity is a serious side effect following anticancer therapy with doxorubicin (Dox) [1,2]
We have recently reported that Dox-induced endoplasmic reticulum (ER) stress in cardiomyocytes is a delayed response of the Bax-mediated cell death process [20]
In the present study on rat heart lysates from Dox-treated rats, we noticed an increase in binding protein (Bip) with a decrease in CCAAT/enhancer-binding homologous protein (CHOP) activation in the heart (Figure 1A)
Summary
Irreversible and life-threatening cardiotoxicity is a serious side effect following anticancer therapy with doxorubicin (Dox) [1,2]. Dox-induced cardiotoxicity is very well characterized, whereby activated oxygen and other reactive oxygen species (ROS) as well as reactive nitrogen species (RNS) are reported to be involved [2,3,4,5,6,7,8,9,10]. ROS as well as RNS are considered as key players in the inhibition of antioxidant enzymes and trigger for the initiation of various cell death pathways such as apoptosis and necrosis [8,11,12,13]. Dox-induced cardiac cell death and ROS production were attenuated by inhibition of NOS3 (eNOS) [9]. Toll-like receptors (TLRs) have been shown to be involved in Dox-induced cardiomyopathy (DIC) where overexpression of TLR2 by Dox treatment worsens the cardiac function [14]
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