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Hydrogen Sulfide Suppresses Diabetic Myocardial ER Stress: An Uncanonical Way
Author(s) -
Veeranki Sudhakar,
Metreveli Naira,
Tyagi Suresh C
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.961.3
Subject(s) - unfolded protein response , medicine , endocrinology , endoplasmic reticulum , diabetic cardiomyopathy , chemistry , atf6 , diabetes mellitus , endoplasmic reticulum associated protein degradation , microbiology and biotechnology , biology , cardiomyopathy , heart failure
Diabetes critically inhibits cardiac endogenous production of hydrogen sulfide (H 2 S), a cardioprotective gaseous signaling molecule, by suppressing expression of CBS, CSE and 3MST (known H 2 S producers endogenously) in the mouse models of type 1 diabetes (Akita or C57BL/6‐Ins2Akita/J). Diabetes induced ER stress has been previously identified as an initiator of cardiomyocyte apoptosis and cardiomyopathy. However, the mechanisms of ER stress induction are not clearly illustrated. Furthermore, H 2 S has been implicated as an inducer or suppressor of ER stress in a tissue type specific manner and molecular mechanisms of H 2 S mediated ER stress regulation are not entirely known. Here, we show that chronic H 2 S supplementation resulted in enhanced cardiac function concurrent with suppression of ER stress with significant reversal of elevated CHOP levels in the diabetic hearts. Interestingly, there were no significant changes in the sXBP1 levels in the diabetic hearts with or without H 2 S treatment suggesting differential regulation of different arms (PERK, ATF6 and IRE1) of ER stress pathway. Importantly, the ER stress suppression is accompanied by suppression of GRP78 (AKA Bip) mRNA levels with a dramatic and paradoxical elevation in its protein levels. Differential translational regulation and/or protein degradation are implicated in regulation of GRP78 protein levels which further highlighted that H 2 S supplementation not only suppresses ER stress, but also raises the threshold for ER stress induction through elevation of GRP78 protein levels. Remarkably, the H 2 S mediated diabetic ER suppression was also accompanied with reversal of elevated TLR4 receptors, a well‐known inducer of ER stress upon stimulation. TLR4 mutant diabetic mice (Akita background) are currently studied to unravel relative contribution of TLR4 dependent and independent mechanisms for H 2 S mediated reversal of ER stress during diabetic cardiomyopathy. In conclusion, H 2 S mediated raise in threshold for ER stress induction involve GRP78 protein preservation and TLR4 level suppression in the diabetic hearts. Support or Funding Information NIH grants : HL108621 , HL074185 and DK104653 .