Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases

Abstract

Despite an obnoxious smell and toxicity at a high dose, hydrogen sulfide (H2S) is emerging as a cardioprotective gasotransmitter. H2S mitigates pathological cardiac remodeling by regulating several cellular processes including fibrosis, hypertrophy, apoptosis, and inflammation. These encouraging findings in rodents led to initiation of a clinical trial using a H2S donor in heart failure patients. However, the underlying molecular mechanisms by which H2S mitigates cardiac remodeling are not completely understood. Empirical evidence suggest that H2S may regulate signaling pathways either by directly influencing a gene in the cascade or interacting with nitric oxide (another cardioprotective gasotransmitter) or both. Recent studies revealed that H2S may ameliorate cardiac dysfunction by up- or downregulating specific microRNAs. MicroRNAs are noncoding, conserved, regulatory RNAs that modulate gene expression mostly by translational inhibition and are emerging as a therapeutic target for cardiovascular disease (CVD). Few microRNAs also regulate H2S biosynthesis. The inter-regulation of microRNAs and H2S opens a new avenue for exploring the H2S-microRNA crosstalk in CVD. This review embodies regulatory mechanisms that maintain the physiological level of H2S, exogenous H2S donors used for increasing the tissue levels of H2S, H2S-mediated regulation of CVD, H2S-microRNAs crosstalk in relation to the pathophysiology of heart disease, clinical trials on H2S, and future perspectives for H2S as a therapeutic agent for heart failure.

Keywords: apoptosis; clinical trial; fibrosis; heart failure; inflammation; microRNAs.

Fig. 1.

Biosynthesis of hydrogen sulfide (H₂S). H₂S production is catalyzed by cystathionine β synthase (CBS), cystathionine gamma lyase (CSE), and the coupling of cysteine aminotransferase (CAT) and 3-mercaptopyruvate sulfur transferase (3-MST). CBS and CSE are involved in transsulfuration of homocysteine, which ultimately generates H₂S. Both enzymes can also convert homocysteine into homolanthionine and H₂S, and cysteine into lanthionine and H₂S. CSE converts homocysteine, cystathionine, and cysteine into H₂S and different by-products. 3-MST and CAT are mostly involved in converting 3-mercaptopyruvate into H₂S in mitochondria. The main pathway of H₂S generation is denoted by large print, whereas additional substrates and products by small print.

Fig. 2.

Cellular catabolism of H₂S. In mitochondria, sulfide quinone oxidoreductase (SQR) oxidizes H₂S to glutathione persulfide (GSSH) with GSH as the electron acceptor or directly to thiosulfate (SO₃²⁻) using co-enzyme Q (Co-Q) as the electron acceptor. The enzymes SOD, sulfur transferase (ST), and sulfite oxidase (SO) further oxidize GSSH to thiosulfate or sulfate, which is excreted via the kidneys. Expiration of H₂S through exhaled air and scavenging by methemoglobin to sulfhemoglobin are alternative methods of H₂S catabolism.

Fig. 3.

Cardioprotective effects of H₂S. The pathways involved in H₂S cardioprotection and the signaling mechanisms that have been shown to be induced (↑) or downregulated/blocked (↓) by H₂S are indicated. The signaling molecules involved in each pathway and their references are included. CTGF, connective tissue growth factor; NOX, NADPH oxidase; SMA, smooth muscle actin; NO, nitric oxide; ROS, reactive oxygen species; ER, endoplasmic reticulum.

Fig. 4.

Interactions between H₂S and microRNAs (miRNAs). MiR-21 and miR-22 inhibit specificity protein 1 [SP1, a transcription factor for cystathionine gamma lyase (CSE)], whereas miR-30 directly inhibits CSE, an enzyme responsible for H₂S production, resulting in decreased H₂S levels. Estrogen (E) activates estrogen receptor α (ERα), which binds to SP1 increasing CSE production and H₂S. ERα also inhibits miR-22, which is an inhibitor of SP1. MiR-22 may also inhibit ERα, providing a secondary pathway for reducing CSE expression. H₂S inhibits miRNAs including miR-221 (anti-neovasculogenic miRNA) and induces miR-133a (antihypertrophy and antifibrotic miRNA). H₂S may inhibit and/or induce miR-21, which is a prohypertrophic miRNA but protects the heart during ischemia-reperfusion injury. H₂S and miR-21 have crosstalk as miR-21 regulates H₂S biosynthesis by inhibiting SP1 and CSE. H₂S regulates Bcl-2 (anti-apoptosis) and Akt (anti-oxidant) either directly or via regulating miR-1 and miR-21, respectively. H₂S may have synergistic effect on these pathways by direct regulation and indirect via miRNA regulation. PTEN, phosphatase and tensin homolog.