Background and Aims
Protein S‐sulfhydration mediated by H2S has been shown to play important roles in several diseases. However, its precise role in liver disease and the related mechanism remain unclear.
Approach and Results
We showed that in streptozotocin (STZ)–treated and high‐fat diet (HFD)–treated low‐density lipoprotein receptor–negative (LDLr−/−) mice, the H2S donor GYY4137 ameliorated liver injury, decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, mitigated lipid deposition, and reduced hepatocyte death. Strikingly, S‐sulfhydration of Kelch‐like ECH‐associated protein 1 (Keap1) was decreased in the livers of patients with fatty liver under diabetic conditions. In STZ+HFD‐treated LDLr−/− mice and in high glucose–treated and oxidized low‐density lipoprotein (ox‐LDL)–treated primary mouse hepatocytes, the GYY4137‐mediated increase in Keap1 S‐sulfhydration induced nuclear erythroid 2‐related factor 2 (Nrf2) dissociation from Keap1, which enhanced the nuclear translocation of Nrf2 itself and the consequent expression of antioxidant proteins. Keap1 Cys151 mutation significantly reduced Keap1 S‐sulfhydration and abolished the hepatoprotective effects of H2S both in vivo and in vitro. Nrf2 deficiency inhibited the H2S‐induced beneficial impacts in Nrf2−/− mice. Similarly, in CCl4‐stimulated mice, GYY4137 increased Keap1 S‐sulfhydration, improved liver function, alleviated liver fibrosis, decreased hepatic oxidative stress, and activated the Nrf2 signaling pathway; and these effects were abrogated after Keap1 Cys151 mutation. Moreover, H2S increased the binding of Nrf2 to the promoter region of LDLr‐related protein 1 (Lrp1) and consequently up‐regulated LRP1 expression, but these effects were disrupted by Keap1 Cys151 mutation.
Conclusions
H2S‐mediated Keap1 S‐sulfhydration alleviates liver damage through activation of Nrf2. Hence, administration of exogenous H2S in the form of the H2S donor GYY4137 may be of therapeutic benefit in the context of concurrent hyperlipidemia and hyperglycemia–induced or CCl4‐stimulated liver dysfunction.
Background:
Cardiac hypertrophy is an important pre-pathology of heart failure, which will ultimately lead to heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. The aim of this study is to elucidate the effects and mechanisms of histidine triad nucleotide binding protein 1 (HINT1) in cardiac hypertrophy and heart failure.
Methods:
HINT1 was down-regulated in human hypertrophic heart samples compared with non-hypertrophic samples by mass spectrometry analysis.
Hint1
knockout mice were challenged with TAC (transverse aortic constriction) surgery. Cardiac specific overexpression of HINT1 mice by intravenous injection of adeno-associated viral (AAV9) encoding Hint1 under the cardiac troponin T (cTnT) promoter were subjected to TAC. Unbiased transcriptional analyses were used to identify the downstream targets of HINT1. AAV9 bearing shRNA against
Homeobox A5
(
Hoxa5
) was administrated to investigate whether the effects of
HINT1
on cardiac hypertrophy were HOXA5 dependent. RNA-Seq analysis was performed to recapitulate possible changes in transcriptome profile. Co-immunoprecipitation assays and cellular fractionation analyses were conducted to examine the mechanism by which HINT1 regulates the expression of HOXA5.
Results:
The reduction of HINT1 expression was observed in the hearts from hypertrophic patients and pressure overloaded-induced hypertrophic mice, respectively. In
Hint1
deficient mice, cardiac hypertrophy was deteriorated after TAC. Conversely, cardiac specific overexpression of HINT1 alleviated cardiac hypertrophy and dysfunction. Unbiased profiler PCR-array showed Homeobox A5 (HOXA5) is one target for HINT1, and the cardioprotective role of HINT1 was abolished by HOXA5 knockdown
in vivo
. Hoxa5 was identified to affect hypertrophy through TGF-β signal pathway. Mechanically, HINT1 inhibited PKCβ1 membrane translocation and phosphorylation via direct interaction, attenuating MEK/ERK/YY1 signal pathway, down-regulating HOXA5 expression and eventually attenuating cardiac hypertrophy.
Conclusions:
HINT1 protects against cardiac hypertrophy through suppressing HOXA5 expression. These findings indicate that HINT1 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.
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