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Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H 2 S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H 2 S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H 2 S in the murine model of chronic DoIC. Application of NaHS, an H 2 S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Cse f/f /Cre + ) to abolish the cardiac synthesis of endogenous H 2 S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Cse f/f /Cre + mice with DoIC, as compared to Cse f/f /Cre - mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H 2 S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Increasing evidence has proposed that mitochondrial abnormalities may be an important factor contributing to the development of heart failure with preserved ejection fraction (HFpEF). Hydrogen sulfide (H 2 S) has been suggested to play a pivotal role in regulating mitochondrial function. Therefore, the present study was designed to explore the protective effect of H 2 S on mitochondrial dysfunction in a multifactorial mouse model of HFpEF., Methods: Wild type, 8-week-old, male C57BL/6J mice or cardiomyocyte specific-Cse (Cystathionine γ-lyase, a major H 2 S-producing enzyme) knockout mice (CSE cko ) were given high-fat diet (HFD) and l-NAME (an inhibitor of constitutive nitric oxide synthases) or standardized chow. After 4 weeks, mice were randomly administered with NaHS (a conventional H 2 S donor), ZLN005 (a potent transcriptional activator of PGC-1α) or vehicle. After additional 4 weeks, echocardiogram and mitochondrial function were evaluated. Expression of PGC-1α, NRF1 and TFAM in cardiomyocytes was assayed by Western blot., Results: Challenging with HFD and l-NAME in mice not only caused HFpEF but also inhibited the production of endogenous H 2 S in a time-dependent manner. Meanwhile the expression of PGC-1α and mitochondrial function in cardiomyocytes were impaired. Supplementation with NaHS not only upregulated the expression of PGC-1α, NRF1 and TFAM in cardiomyocytes but also restored mitochondrial function and ultrastructure, conferring an obvious improvement in cardiac diastolic function. In contrast, cardiac deletion of CSE gene aggravated the inhibition of PGC-1α-NRF1-TFAM pathway, mitochondrial abnormalities and diastolic dysfunction. The deleterious effect observed in CSE cko HFpEF mice was partially counteracted by pre-treatment with ZLN005 or supplementation with NaHS., Conclusion: Our findings have demonstrated that H 2 S ameliorates left ventricular diastolic dysfunction by restoring mitochondrial abnormalities via upregulating PGC-1α and its downstream targets NRF1 and TFAM, suggesting the therapeutic potential of H 2 S supplementation in multifactorial HFpEF., Competing Interests: Declaration of competing interest The authors declares that there is no conflict of interest regarding the publication of this article., (Copyright © 2023. Published by Elsevier Inc.)

Endothelial‑to‑mesenchymal transition (EndMT) serves an important role in the vascular remodeling of pulmonary arterial hypertension (PAH). However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in PAH and the process of EndMT. Male Sprague‑Dawley rats (10 weeks old) received a single dose of monocrotaline (MCT; i.p., 60 mg/kg) and were randomly treated with NaHS [an H2S donor; intraperitoneal (i.p.) 1 mg/kg/day], DL‑propagylglycine (an inhibitor of H2S synthesis; PAG; i.p., 10 mg/kg/day) or saline, 7 days after MCT injection. Rats were sacrificed 21 days after MCT injection. A selection of human pulmonary artery endothelial cells (HPAECs) were pretreated with NaHS or saline and stimulated with transforming growth factor (TGF)‑β1 (10 ng/ml), and the other HPAECs were transfected with a cystathionine γ‑lyase (CSE, an H2S synthesizing enzyme) plasmid and subsequently stimulated with TGF‑β1. NaHS was indicated to inhibit EndMT and PAH progression by inhibiting the induction of the nuclear factor (NF)‑κB‑Snail pathway. In contrast, the depletion of H2S formation by PAG exacerbated EndMT and PAH by activating NF‑κB‑Snail molecules. In HPAECs, NaHS dose‑dependently inhibited TGF‑β1‑induced EndMT and the activation of the NF‑κB‑Snail pathway. Transfection with a CSE plasmid significantly repressed TGF‑β1‑induced expression of the mesenchymal marker and upregulated the expression of the endothelial marker, which was accompanied by the suppression of the NF‑κB‑Snail pathway. The inhibitory effect of CSE overexpression on TGF‑β1‑induced EndMT was significantly reversed by pretreatment with PAG. In conclusion, the current study provides novel information elucidating the beneficial effect of H2S on PAH through inhibiting the induction of the NF‑κB‑Snail pathway and the subsequent process of EndMT in pulmonary arteries.

Hydrogen sulfide (H2S) functions as a protective gas transmitter in various physiological and pathological processes, but the lack of ideal donors severely hampers the clinical application of H2S. This study aims to construct a controlled release H2S donor and evaluate its protective effect on graft endothelium. Mesoporous silica nanoparticles (MSNs) were synthesized using the sol-gel method and loaded with diallyl trisulfide (DATS), an H2S-releasing agent named DATS-MSN. In vitro experiments showed that DATS-MSN could alleviate endothelial cell inflammation and enhance endothelial cell proliferation and migration. In vivo experiments demonstrated that the apoptosis of graft endothelium was mitigated in the presence of DATS-MSN. Our results indicated that DATS-MSN, releasing H2S in a controlled release fashion, could serve as an ideal H2S donor.

Objectives: Recent data in human and mice suggest that monocyte chemokine receptors CX3CR1 and CCR2 are involved in the pathogenesis of atherosclerosis. Our previous study showed that hydrogen sulfide, a novel gaseous mediator hampered the progression of atherosclerosis in fat-fed apoE(-/-) mice with downregulating CX3CR1 and CX3CL1 expressions. However, there is a paucity of information regarding the clinical association between endogenous H2S metabolism and alterations of monocyte chemokine receptors in patients with cardiovascular disease. Therefore, in this study, we investigated circulating monocyte heterogeneity with differential expressions of CCR2 and CX3CR1 and its relevance to plasma H2S level in patients with coronary artery disease (CAD)., Methods: Sixty-three CAD patients with acute coronary syndrome (ACS, n = 46) or stable angina pectoris (SAP, n = 17) undergoing either percutaneous coronary intervention or coronary angiography and eleven non-CAD patients were enrolled in the study. Plasma levels of H2S as well as chemokines (CCL2 and CX3CL1) and expressions of CCR2 and CX3CR1 on peripheral monocytes were measured., Results: It was found that plasma H2S level was significantly reduced, whereas plasma CCL2 and CX3CL1 levels were substantially elevated in patients with ACS, as compared with patients with SAP or non-CAD patients. Furthermore, patients with ACS had significantly higher proportion of CD14(+)CCR2(+)CX3CR1(+) and CD14(+)CCR2(-)CX3CR1(+) monocytes but lower percentage of CD14(+)CCR2(+)CX3CR1(-) monocytes than SAP or non-CAD patients did. Lastly, plasma H2S level showed a significantly negative correlation with the proportion of CD14(+)CCR2(+)CX3CR1(+) monocytes, but not other monocyte subsets., Conclusions: These data indicate that decreased endogenous H2S production may predispose stable CAD patients to rupture of vulnerable plaque and thus to ACS, probably in relation to circulating monocyte phenotypic transformation with differential expressions of CCR2 and CX3CR1.

Background: Hydrogen sulfide (H2S), as a newly identified gaseous mediator, has been widely investigated in various systems. However, the effect of H2S on cardiovascular system haemostasis, including platelet aggregation and the precise mechanisms remain unclear. Therefore, the present study was aimed to examine the inhibitory effect of H2S on human platelet aggregation in vitro and its relevance to gap junction channels., Methods and Results: The antiaggregatory property of H2S-releasing aspirin derivative (ACS14) was compared with its mother compound, aspirin. In comparison to an equimolar dose of aspirin, ACS14 not only exerted a more potent inhibitory effect on platelet aggregation induced by ADP or thrombin, but also significantly inhibited αIIbβ3 integrin activation and P-selectin expression. Similarly, NaHS (100μM), a conventional H2S donor significantly inhibited platelet aggregation as well as αIIbβ3 integrin activation and P-selectin expression induced by ADP or thrombin. Furthermore, pretreatment with rotigaptide, a gap junction modifier abolished the inhibitory properties of ACS14 or NaHS on platelet aggregation, suggesting that suppression of platelet aggregation by H2S is, at least in part, gap junction channel-dependent., Conclusions: H2S may inhibit human platelet aggregation at least in part by depressing gap junction intercellular communication and H2S released from ACS14 may contribute to its additional anti-platelet effect in vitro in comparison to aspirin., (Copyright © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)