H 2 S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes

Hydrogen sulfide (H S), a cardioprotective gas, is endogenously produced from homocysteine by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE) enzymes. However, effect of H S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesiz...

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Bibliographic Details
Published in:Scientific reports 2017-06, Vol.7 (1), p.3639
Main Authors: Nandi, Shyam Sundar, Mishra, Paras Kumar
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Animals
Cystathionine - metabolism
Cystathionine beta-Synthase - genetics
Cystathionine beta-Synthase - metabolism
Cystathionine gamma-Lyase - genetics
Cystathionine gamma-Lyase - metabolism
Dose-Response Relationship, Drug
Feedback, Physiological
Female
Gene Expression Regulation
Homocysteine - pharmacology
Hydrogen Sulfide - pharmacology
Male
Mice
Mice, Knockout
MicroRNAs - genetics
Models, Biological
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
RNA Interference
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Summary:Hydrogen sulfide (H S), a cardioprotective gas, is endogenously produced from homocysteine by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE) enzymes. However, effect of H S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesize that homocysteine and H S regulate CBS and CSE expressions in a dose dependent manner in cardiomyocytes, and CBS deficiency induces cardiac CSE expression. To test the hypothesis, we treated murine atrial HL1 cardiomyocytes with increasing doses of homocysteine or Na S/GYY4137, a H S donor, and measured the levels of CBS and CSE. We found that homocysteine upregulates CSE but downregulates CBS whereas Na S/GYY4137 downregulates CSE but upregulates CBS in a dose-dependent manner. Moreover, the Na S-treatment downregulates specificity protein-1 (SP1), an inducer for CSE, and upregulates miR-133a that targets SP1 and inhibits cardiomyocytes hypertrophy. Conversely, in the homocysteine-treated cardiomyocytes, CBS and miR-133a were downregulated and hypertrophy was induced. In vivo studies using CBS+/-, a model for hyperhomocysteinemia, and sibling CBS+/+ control mice revealed that deficiency of CBS upregulates cardiac CSE, plausibly by inducing SP1. In conclusion, we revealed a novel mechanism for H S-mediated regulation of homocysteine metabolism in cardiomyocytes, and a negative feedback regulation between CBS and CSE in the heart.
ISSN:2045-2322