Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes

Abstract

An elevated level of homocysteine called hyperhomocysteinemia (HHcy) is associated with pathological cardiac remodeling. Hydrogen sulfide (H2S) acts as a cardioprotective gas, however the mechanism by which H2S mitigates homocysteine mediated pathological remodeling in cardiomyocytes is unclear. We hypothesized that H2S ameliorates HHcy mediated hypertrophy by inducing cardioprotective miR-133a in cardiomyocytes. To test the hypothesis, HL1 cardiomyocytes were treated with: 1) plain medium (control, CT), 2) 100μM of homocysteine (Hcy), 3) Hcy with 30μM of H2S (Hcy+H2S), and 4) H2S for 24 hour. The levels of hypertrophy markers: c-fos, atrial natriuretic peptide (ANP), and beta-myosin heavy chain (β-MHC), miR-133a and its transcriptional inducer myosin enhancer factor- 2c (MEF2C) were determined by Western blotting, RT-qPCR, and immunofluorescence. The activity of MEF2C was assessed by co-immunoprecipitation of MEF2C with histone deacetylase -1(HDAC1). Our results show that H2S ameliorates homocysteine mediated up regulation of c-fos, ANP and β-MHC, and down regulation of MEF2C and miR-133a. HHcy induces the binding of MEF2C with HDAC1, whereas H2S releases MEF2C from MEF2C-HDAC1 complex causing activation of MEF2C. These findings elicit that HHcy induces cardiac hypertrophy by promoting MEF2C-HDAC1 complex formation that inactivates MEF2C causing suppression of anti-hypertrophy miR-133a in cardiomyocytes. H2S mitigates hypertrophy by inducing miR-133a through activation of MEF2C in HHcy cardiomyocytes. To our knowledge this is a novel mechanism of H2S mediated activation of MEF2C and induction of miR-133a and inhibition of hypertrophy in HHcy cardiomyocytes.

Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases

“…The H 2 S donor SG1002 prevents cardiac hypertrophy and cardiac dysfunction by reducing endoplasmic reticulum stress in high-fat diet-fed mice (9). Our laboratory has demonstrated that H 2 S treatment mitigates cardiac hypertrophy by upregulating miR-133a (73), an antihypertrophy (24, 41) and antifibrosis (28, 101) microRNA. To increase the levels of miR-133a, H 2 S activates myosin enhancer factor-2c (MEF2C), a transcription factor of miR-133a, by releasing MEF2C from MEF2C-HDAC1 complex (inactivated state) (73).…”

“…Our laboratory has demonstrated that H 2 S treatment mitigates cardiac hypertrophy by upregulating miR-133a (73), an antihypertrophy (24, 41) and antifibrosis (28, 101) microRNA. To increase the levels of miR-133a, H 2 S activates myosin enhancer factor-2c (MEF2C), a transcription factor of miR-133a, by releasing MEF2C from MEF2C-HDAC1 complex (inactivated state) (73). These studies suggest that H 2 S plays a crucial role in inhibiting cardiac hypertrophy (Fig.…”

“…Evidence is mounting that H 2 S is important in reducing the symptoms associated with CVD. H 2 S reduces hypertension (2, 3), improves glucose uptake and metabolism (9, 89), protects against ischemia-reperfusion (I/R) injury (70,81,141,161), and decreases cardiac hypertrophy (9,73,93,97). Further evidence shows that free H 2 S levels are reduced in patients with CVD (64,79,118), suggesting H 2 S supplementation may be a potential therapy for mitigating CVD.…”

The role of hydrogen sulfide in homocysteine-induced cardiodynamic effects and oxidative stress markers in the isolated rat heart

“…For this reason, hyperhomocysteinemia (HHcy) is suggested as a new and independent risk factor for developing these conditions (38,39). HHcy occurs as a consequence of an impaired remethylation process or a deficiency in Hcy metabolic enzymes [cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfur transferase] (19). These three enzymes break down Hcy into hydrogen sulfide (H 2 S) (33).…”

“…H 2 S acts as a vasorelaxant (45) and an inhibitor of hypertrophy and fibrosis of vascular smooth muscle cells (17). Taking into consideration that HHcy can be caused by the inhibition of metabolic enzymes that produce H 2 S from Hcy (19), the question arises whether the blockade of H 2 S synthesis influence homocysteine-induced cardiac effects.…”