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

• DOI: 10.1161/jaha.116.004160
• Publication Date: 2016-09-17T01:10:39Z
• 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
• Keywords: Male; myocardial hypertrophy; Morpholines; hydrogen sulfide; Kruppel-Like Transcription Factors; 610; Cardiomegaly; 03 medical and health sciences; Rats, Inbred SHR; atrial natriuretic peptide; Diseases of the circulatory (Cardiovascular) system; Animals; Humans; Myocytes, Cardiac; Hydrogen Sulfide; RNA, Messenger; Specificity protein 1; S‐sulfhydration; Atrial natriuretic peptide; specificity protein 1; Krüppel‐like factor 5; Original Research; Platelet-Derived Growth Factor; 0303 health sciences; Hydrogen sulfide; Angiotensin II; Myocardium; Cystathionine gamma-Lyase; Krüppel-like factor 5; Organothiophosphorus Compounds; Myocardial hypertrophy; S-sulfhydration; Rats; 3. Good health; Animals, Newborn; Gene Expression Regulation; RC666-701; Case-Control Studies; Atrial Natriuretic Factor

Background

Hydrogen sulfide (H 2 S) is a gasotransmitter that regulates multiple cardiovascular functions. Krüppel‐like factor 5 (KLF5) exerts diverse functions in the cardiovascular system. Whether and how H 2 S 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 H 2 S‐releasing compound. Expression of cystathionine γ‐lyase, a principal enzyme for H 2 S 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. H 2 S diminished expression of KLF5 in myocardium of spontaneously hypertensive rats and in hypertrophic cardiomyocytes. H 2 S 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 H 2 S. H 2 S increased the S‐sulfhydration on specificity protein 1 in cardiomyocytes. Moreover, H 2 S 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 H 2 S regulates KLF5 transcription activity via specificity protein 1 S‐sulfhydration at Cys664 to prevent myocardial hypertrophy.