S-diclofenac Protects against Doxorubicin-Induced Cardiomyopathy in Mice via Ameliorating Cardiac Gap Junction Remodeling

Abstract

Hydrogen sulfide (H2S), as a novel gaseous mediator, plays important roles in mammalian cardiovascular tissues. In the present study, we investigated the cardioprotective effect of S-diclofenac (2-[(2,6-dichlorophenyl)amino] benzeneacetic acid 4-(3H-1,2,dithiol-3-thione-5-yl)phenyl ester), a novel H2S-releasing derivative of diclofenac, in a murine model of doxorubicin-induced cardiomyopathy. After a single dose injection of doxorubicin (15 mg/kg, i.p.), male C57BL/6J mice were given daily treatment of S-diclofenac (25 and 50 µmol/kg, i.p.), diclofenac (25 and 50 µmol/kg, i.p.), NaHS (50 µmol/kg, i.p.), or same volume of vehicle. The cardioprotective effect of S-diclofenac was observed after 14 days. It showed that S-diclofenac, but not diclofenac, dose-dependently inhibited the doxorubicin-induced downregulation of cardiac gap junction proteins (connexin 43 and connexin 45) and thus reversed the remodeling of gap junctions in hearts. It also dose-dependently suppressed doxorubicin-induced activation of JNK in hearts. Furthermore, S-diclofenac produced a dose-dependent anti-inflammatory and anti-oxidative effect in this model. As a result, S-diclofenac significantly attenuated doxorubicin-related cardiac injury and cardiac dysfunction, and improved the survival rate of mice with doxorubicin-induced cardiomyopathy. These effects of S-diclofenac were mimicked in large part by NaHS. Therefore, we propose that H2S released from S-diclofenac in vivo contributes to the protective effect in doxorubicin-induced cardiomyopathy. These data also provide evidence for a critical role of H2S in the pathogenesis of doxorubicin-induced cardiomyopathy.

Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

“…First, H 2 S is a major endothelium-derived hyperpolarizing factor (EDHF) that causes hyperpolarization and vasorelaxation of vascular endothelium and smooth muscle cells by activating ATPsensitive, intermediate-conductance and small-conductance potassium channels through cysteine S-sulfhydration (19,20). Second, H 2 S can prevent cytokine-or oxidant-induced oxidative damage through its antioxidative effects (21)(22)(23). Additionally, H 2 S can inhibit the expression of proinflammatory factors by downregulating NF-B activation or by upregulating heme oxygenase 1 expression (24-28).…”

Pathophysiology of cancer therapy-provoked atrial fibrillation

“…Dogs treated with doxorubicin showed several ECG abnormalities including ST segment elevation, QT intervals prolongation, inverted T wave, arrhythmia and myocardial ischemia [95]. Previous studies recognized that doxorubicin can lead to progressive cardiac dysfunction and LV remodeling through down-regulation of cardiac expression Cx43/Cx45 junction channels [92]. Doxorubicin-induced mitochondrial dysfunction [82], oxidative stress [96], and cellular apoptosis were identified in cardiomyocytes [97].…”

“…Doxorubicin, widely used to treat a variety of human cancers, was demonstrated to mediate dose-related cardiotoxicity including transient electrocardiographic abnormalities, cardiomyopathy, and HF [92]. Kilickap et al recorded paroxysmal AF in 10.3% of 29 patients during the first course of doxorubicin-containing chemotherapy [93].…”

Hydrogen Sulfide in Renal Physiology and Disease

“…Doxorubicin may cause congestive heart failure and chronic kidney injury in the form of focal segmental sclerosis of the glomerulus that is associated with marked proteinuria and loss of clearance function of the kidney (51). H2S has been proposed as a mediator of kidney injury manifesting as inflammation and proteinuria after the administration of doxorubicin (22); however, H2S donors have been shown to protect the heart from doxorubicin-induced toxicity (102), suggesting the need for clarification of the role of H2S in kidney injury induced by that agent. In addition, studies are also needed on the involvement of H2S in acute kidney injury due to other nephrotoxic agents such as radiocontrast media containing iodine and gadolinium.…”