Hydrogen Sulfide Regulates Krüppel-Like Factor 5 Transcription Activity via Specificity Protein 1 S-Sulfhydration at Cys664 to Prevent Myocardial Hypertrophy.

Abstract

BACKGROUND:

Hydrogen sulfide (H2S) is a gasotransmitter that regulates multiple cardiovascular functions. Krüppel-like factor 5 (KLF5) exerts diverse functions in the cardiovascular system. Whether and how H2S regulates KLF5 in myocardial hypertrophy is unknown.

METHODS AND RESULTS:

In our study, hypertrophic myocardial samples in the clinic were collected and underwent histological and molecular biological analysis. Spontaneously hypertensive rats and neonatal rat cardiomyocytes were studied for functional and signaling responses to GYY4137, an H2S-releasing compound. Expression of cystathionine γ-lyase, a principal enzyme for H2S generation in heart, decreased in human hypertrophic myocardium, whereas KLF5 expression increased. After GYY4137 administration for 4 weeks, myocardial hypertrophy was inhibited in spontaneously hypertensive rats, as demonstrated by improvement in cardiac structural parameters, heart mass, size of cardiac myocytes, and expression of atrial natriuretic peptide. H2S diminished expression of KLF5 in myocardium of spontaneously hypertensive rats and in hypertrophic cardiomyocytes. H2S also inhibits platelet-derived growth factor A promoter activity, decreased recruitment of KLF5 to the platelet-derived growth factor A promoter, and reduced atrial natriuretic peptide expression in angiotensin II-stimulated cardiomyocytes, and these effects are suppressed by KLF5 knockdown. KLF5 promoter activity and KLF5 expression was also reversed by H2S. H2S increased the S-sulfhydration on specificity protein 1 in cardiomyocytes. Moreover, H2S decreased KLF5 promoter activity; reduced KLF5 mRNA expression; attenuated specificity protein 1 binding activity with KLF5 promoter; and inhibited hypertrophy after specificity protein 1 mutated at Cys659, Cys689, and Cys692 but not Cys664 overexpression.

CONCLUSIONS:

These findings suggest that H2S regulates KLF5 transcription activity via specificity protein 1 S-sulfhydration at Cys664 to prevent myocardial hypertrophy.

• Authors: Guoliang Meng, Yujiao Xiao, Yan Ma, Xin Tang, Liping Xie, Jieqiong Liu, Yue Gu, Ying Yu, Chung-Min Park, Ming Xian, Xin Wang, Albert Ferro, Rui Wang, Philip K Moore, Zhiren Zhang, Hong Wang, Yi Han, Yong Ji
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 5 Issue 9 (09 16 2016) ISSN: 2047-9980 [Electronic] England
• PMID: 27638782 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

• GYY 4137
• KLF5 protein, human
• Klf5 protein, rat
• Kruppel-Like Transcription Factors
• Morpholines
• Organothiophosphorus Compounds
• Platelet-Derived Growth Factor
• RNA, Messenger
• Sp1 Transcription Factor
• platelet-derived growth factor A
• Angiotensin II
• Atrial Natriuretic Factor
• Cystathionine gamma-Lyase
• Hydrogen Sulfide

Topics

• Angiotensin II (blood)
• Animals
• Animals, Newborn
• Atrial Natriuretic Factor (drug effects, metabolism)
• Cardiomegaly (genetics, metabolism)
• Case-Control Studies
• Cystathionine gamma-Lyase (metabolism)
• Gene Expression Regulation (drug effects)
• Humans
• Hydrogen Sulfide (metabolism)
• Kruppel-Like Transcription Factors (drug effects, genetics, metabolism)
• Male
• Morpholines (pharmacology)
• Myocardium (metabolism)
• Myocytes, Cardiac (drug effects, metabolism)
• Organothiophosphorus Compounds (pharmacology)
• Platelet-Derived Growth Factor (drug effects, metabolism)
• RNA, Messenger (drug effects, metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Sprague-Dawley
• Sp1 Transcription Factor (metabolism)
• Transcriptional Activation (drug effects)