Hydrogen Sulfide as a Potential Alternative for the Treatment of Myocardial Fibrosis

Table 1

H₂S donors and their involvement in myocardial fibrosis.

H2S donor (characteristics)	Fibrosis model	Suggested mode of action
Sodium thiosulfate (Na2O3S); (Hydrophilic, fast H2S release)	Hypertension	Antihypertensive activity [99]; ↓Oxidative stress and ↑endogenous H2S production [126]
Sodium hydrosulfide (NaHS); (Hydrophilic, fast H2S release)	Diabetes (type I)	↓Canonical Wnt pathway-TGF-β1/SMAD3 pathway [114]; ↑PKC-ERK1/2MAPK signaling pathway [127]; ↓ER stress [115]; ↓Autophagy via the upregulation of the PI3K/AKT1 pathway [116]
	Diabetes (type II)	↓Cardiac muscle degradation via sulfhydration of MuRF1 [128]
	Hypertension	↓Inflammatory response [103]; ↓Extracellular matrix accumulation and ↑vascular density [129]; ↓Nox4-ROS-ERK1/2 pathway and ↑HO-1 expression [130]; ↑Akt/eNOS/NO pathway [105]; ↓Nitrotyrosine, ↓MMP-2 and MMP-9, and ↑TIMP-1 and TIMP-3 [131]; ↑Opening of KATP channels and ↓oxidative stress [132]
	Myocardial infarction	↓Oxidative stress [133]; ↓iNOS and ↑HO-1 expression [134]; ↓mPTP opening in the aging cardiomyocytes [92]; ↑Glycogen synthase kinase-3β/β-catenin pathway [85]; ↑cGMP-dependent PKG/phospholamban pathway [135]; ↑Angiogenesis [136]; ↑Autophagy in the aged hearts [96]
	Metal toxicity; (e.g., nickel)	↓Sp1 transactivation and ↓TGF-β1/SMAD1 pathway [21]
Sodium sulfide (Na2S) (Hydrophilic, H2S release for ~520 min in vivo; ~5 min in vitro)	Hypertension	↑Vasorelaxation [100, 101]; ↑Trx1 [137]
	Myocardial infarction	↑Mitochondrial function [95]; ↑Nrf2 signaling pathway [87]; ↑miR-21 [91]
GYY4137; (Hydrolysis-triggered H2S release; slow-release and 3–4 h lasting)	Diabetes (type I)	↓FoxO1 pathway [138]; ↑Autophagy via the AMPK/mTOR pathway [112]; ↑Nrf2 pathway mediated by sulfhydration of Keap1 [88]
	Myocardial infarction	↑PKG I [139]; ↓Oxidative stress and ↓apoptosis [140, 141]
AP67/AP72; (Slow-releasing H2S donors)	Atherosclerosis	↓Calcification effects in heart valves [142]
AP39; (Mitochondria-targeted H2S)	Myocardial infarction	↓mPTP opening [93, 94]; ↓Cardiomyocyte death and ↓inflammatory response [143]
SG-1002; (Orally active)	Hypertension	↑VEGF-Akt-eNOS-NO-cGMP signaling pathway [144]
	Myocardial dysfunction	↑Adiponectin-AMPK signaling and ↓ER stress [19]
		↑NO bioavailability [145]
Diallyl disulfide (DAD) [146]; (Organosulfur compound; insoluble in water; slow H2S donor [146])	Myocardial infarction	↓ER stress via SIRT1 [147]; ↑AMPK-mediated AKT/GSK-3β/HIF-1α activation [148]
Diallyl trisulfide (DAT) [146]; (Organosulfur compound; fast H2S donor)	Hyperglycemia	↑PI3K/Akt/Nrf2 pathway [89]; ↓JNK/NF-κβ pathway [149]
ADT-OH; (H2S-aspirin hybrid molecule)	Myocardial infarction	↑Autophagic flux via activating AMPK [94]
ZYZ-803; (H2S-NO hybrid molecule)	Adrenergic overload	↑Activation of VEGF/cGMP pathway [86]
ZYZ-802; (S-Propargyl-cysteine; cysteine derivatives)	Hypertension	↓Oxidative stress and ↓cardiomyocyte death [104]
	Myocardial infarction	↓miRNA-30 family [16]

Abbreviations: AMPK: AMP-activated protein kinase; Ang-II: angiotensin-II; cGMP: cyclic guanosine monophosphate; ECM: extracellular matrix; eNOS: endothelial nitric oxide synthase; ER: endoplasmic reticulum; ERK: extracellular-signal-regulated kinase; FoxO1: transcription factor Forkhead 1; GSK-3β: glycogen synthase kinase-3β; H₂S: hydrogen sulfide; HIF-1α: hypoxia-inducible factor-1α; HO-1: heme oxygenase-1; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinase; Keap1: Kelch-like ECH-associated protein 1; MAPK: mitogen-activated protein kinase; MI: myocardial infarction; miRNA: microRNA; MMP: matrix metalloproteinase; mPTP: mitochondrial permeability transition pore; NOX4: NADPH oxidase 4; MuRF1: muscle RING-finger protein-1; NF-κβ: nuclear factor kappa light chain enhancer of activated B cell; Nrf2: nuclear factor E2-related factor 2; PI3K: phosphoinositide 3-kinases; PKC: protein kinase C; PKG: protein kinase G; SIRT1: sirtuin 1; SMAD: mothers against decapentaplegic homolog; Sp1: specificity protein 1; TGF-β: transforming growth factor-β; TIMP: tissue inhibitor of metalloproteinase; Trx1: thioredoxin 1; VEGF: vascular endothelial growth factor. ↓ and ↑ denote inhibition or suppression and increase or activation, respectively.