Thioredoxin 1 Is Essential for Sodium Sulfide–Mediated Cardioprotection in the Setting of Heart Failure

Abstract

Objective The aim of this study was to determine if thioredoxin-1 (Trx1) mediates the cardioprotective effects of hydrogen sulfide (H2S) in a model of ischemic-induced heart failure. Approach/Results Mice with a cardiac-specific overexpression of a dominant negative mutant of Trx1 (Tg-DN-Trx1) and wild-type littermates were subjected to ischemic-induced heart failure. Treatment with H2S as sodium sulfide (Na2S) not only increased the gene and protein expression of Trx1 in the absence of ischemia, but also augmented the heart failure-induced increase in both. Wild-type mice treated with Na2S experienced less left ventricular (LV) dilatation, improved LV function, and less cardiac hypertrophy after the induction of heart failure. In contrast, Na2S therapy failed to improve any of these parameters in the Tg-DN-Trx1 mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S therapy inhibited heart failure-induced apoptosis signaling kinase-1 (ASK1) signaling and nuclear export of histone deacetylase 4 (HDAC4) in a Trx1-dependent manner. Conclusions These findings provide novel information that the upregulation of Trx1 by Na2S therapy in the setting of heart failure sets into motion events, such as the inhibition of ASK1 signaling and HDAC4 nuclear export, which ultimately leads to the attenuation of LV remodeling.

Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress

“…Hydrogen sulfide and sulfane sulfur levels were measured in the heart and blood according to previously described methods [38]. For heart tissue, the amount of H 2 S is reported as nmol/mg wet weight.…”

“…Cell surface area (μm 2 ) and cross-sectional area (μm 2 ) were analyzed by staining cardiac cryosections with wheat germ agglutinin (WGA)-Texas Red-X conjugate (Life Technologies) as described previously to show myocyte membranes in histological sections [38]. Paraffin fixed slides were deparaffinized, washed in 1XPBS and then incubated in 10μg WGA-Texas Red-X conjugate for 1 hour at room temperature followed by additional washes in 1XPBS.…”

“…Western blot analysis was performed as described previously [38]. Protein concentrations were measured with the DC protein assay (Bio-Rad Laboratories, Hercules, CA, USA).…”

Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor‐Erythroid 2‐Related Factor 2 (Nrf2)‐Dependent Signaling in Chronic Heart Failure

“…In particular, H 2 S stimulates Nrf2 activation and blunts NOX1 (NADPH oxidase 1) expression and activity,63 leading to increased anti‐oxidant defense responses,34 resulting in the protection of cardiac cells from oxidative injury. Nrf2 and its downstream gene targets play important roles in protecting the heart from ischemic injury via suppressing oxidative stress/ROS, as well as from maladaptive remodeling and cardiac dysfunction 64, 65, 66, 67. For instance, Nrf2 KO mice display exacerbated cardiac injury in response to acute myocardial I/R injury 34.…”

Thioredoxin Superfamily and Its Effects on Cardiac Physiology and Pathology

“…The expression levels of Trx1 in the heart are upregulated in pathological conditions such as ischemic preconditioning (181), pressure overload (203), myocarditis (114,153), adriamycin-induced cardiotoxicity (152), and under the sodium sulfide therapy (123), which contribute to the reduction of both oxidative stress and cardiomyocyte apoptosis. Studies of animal models of ischemia reperfusion injury show that increasing the level of Trx1, either by transgenic overexpression or intravenous administration of recombinant Trx1 protein, reduces markers of tissue damage in the heart (181), kidney (77), and brain (55).…”