Fig 4 - uploaded by Rebecca Hood
Content may be subject to copyright.
Na2S increases the nuclear expression of nuclear factor E2-related factor (Nrf2). A: representative immunoblots and densitometric analysis of whole cell and nuclear Nrf2 from the hearts of nondiabetic and diabetic mice. B: representative immunoblots and densitometric analysis of nuclear Nrf2 in the hearts of diabetic mice treated with either a single injection of Na2S (Na2S acute) or with daily injections for 7 days (Na2S 7d). C: representative immunoblots and densitometric analysis of NADPH quinine oxidoreductase 1 (NQO1) and heme-oxygenase-1 (HO-1) in the hearts of sham, Na2S acute, and Na2S 7d mice. D: chromatin immunoprecipitation (ChIP) analysis of Nrf2 binding to the NQO1 or HO-1 promoter in the hearts of sham, Na2S acute, and Na2S 7d mice. A parallel ChIP assay was performed with IgG as a ChIP assay control. Data in A were compared with a Student's t-test. All other data were compared through the use of a 1-way ANOVA with a Tukey test as the post hoc analysis. *P 0.05, **P 0.01, and ***P 0.001 vs. sham. IP, immunoprecipitation.
Source publication
Hydrogen sulfide (H2S) therapy protects non-diabetic animals in various models of myocardial injury, including acute myocardial infarction and heart failure. Here, we sought to examine if H2S therapy provides cardioprotection in the setting of Type-2 diabetes. H2S therapy in the form of sodium sulfide (Na2S) beginning 24 hours or 7 days prior to my...
Citations
... Protection against myocardial injury after I/R in db/db diabetic mice (0.1 mg/kg/day) [102]. Protection against myocardial injury in Nrf2-KO and control mice injected with H2S (100 µg/kg) [103]. ...
... In contrast, in wild-type mice subjected to ischemic-induced heart failure, H2S improved Nrf2 signaling, left ventricular function, and reduced cardiac hypertrophy [104]. Similar results were obtained by Peake et al. for db/db diabetic mice after I/R injury [102]. ...
Irisin is a myokine secreted under the influence of physical activity and exposure to low temperatures and through different exogenous stimuli by the cleavage of its precursor, fibronectin type III domain-containing protein 5 (FNDC5). It is mainly known for maintaining of metabolic homeostasis, promoting the browning of white adipose tissue, the thermogenesis process, and glucose homeostasis. Growing experimental evidence suggests the possible central role of irisin in the regulation of cardiometabolic pathophysiological processes. On the other side, hydrogen sulfide (H2S) is well recognized as a pleiotropic gasotransmitter that regulates several homeostatic balances and physiological functions and takes part in the pathogenesis of cardiometabolic diseases. Through the S-persulfidation of cysteine protein residues, H2S is capable of interacting with crucial signaling pathways, exerting beneficial effects in regulating glucose and lipid homeostasis as well. H2S and irisin seem to be intertwined; indeed, recently, H2S was found to regulate irisin secretion by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/FNDC5/irisin signaling pathway, and they share several mechanisms of action. Their involvement in metabolic diseases is confirmed by the detection of their lower circulating levels in obese and diabetic subjects. Along with the importance of metabolic disorders, these modulators exert favorable effects against cardiovascular diseases, preventing incidents of hypertension, atherosclerosis, heart failure, myocardial infarction, and ischemia–reperfusion injury. This review, for the first time, aims to explore the role of H2S and irisin and their possible crosstalk in cardiovascular diseases, pointing out the main effects exerted through the common molecular pathways involved.
... Phosphorylation of ERK1/2 induces the activation of Nrf2 which, in turn, upregulates HO-1 expression [87]. Notably, the removal of Bach1 (HO-1 transcriptional repressor) from the nucleus in an ERK1/2-dependent manner can change the time difference between NAD(P)H quinone dehydrogenase 1 (NQO1) and HO-1 increase after myocardial injury treatment [88]. However, the activation of MAPK signaling pathway does not always exert a protective effect on MIRI. ...
Myocardial ischemia is the leading cause of health loss from cardiovascular disease worldwide. Myocardial ischemia and hypoxia during exercise trigger the risk of sudden exercise death which, in severe cases, will further lead to myocardial infarction. The Nrf2 transcription factor is an important antioxidant regulator that is extensively engaged in biological processes such as oxidative stress, inflammatory response, apoptosis, and mitochondrial malfunction. It has a significant role in the prevention and treatment of several cardiovascular illnesses, since it can control not only the expression of several antioxidant genes, but also the target genes of associated pathological processes. Therefore, targeting Nrf2 will have great potential in the treatment of myocardial ischemic injury. Natural products are widely used to treat myocardial ischemic diseases because of their few side effects. A large number of studies have shown that the Nrf2 transcription factor can be used as an important way for natural products to alleviate myocardial ischemia. However, the specific role and related mechanism of Nrf2 in mediating natural products in the treatment of myocardial ischemia is still unclear. Therefore, this review combs the key role and possible mechanism of Nrf2 in myocardial ischemic injury, and emphatically summarizes the significant role of natural products in treating myocardial ischemic symptoms, thus providing a broad foundation for clinical transformation.
... In the effective range column, green indicates low, physiological doses of the compound required to elicit therapeutic effects, whereas orange > red indicate doses approaching/beyond endogenous H 2 S levels. Note: the clinically tested molecules ATTM, Zofenopril are in trials for mechanisms separate to H 2 S release [93][94][95][96][97][98][99][100][101][102][103][104][106][107][108][109][110][111][112][113][114][115]117,118]. ...
... Our laboratory has long been involved in researching the role of hydrogen sul de in improving myocardial brosis. Several studies, including ours, have suggested that hydrogen sul de may ameliorate diabetic cardiomyopathy, hypertension-induced myocardial brosis in rats following abdominal aortic constriction surgery, and myocardial injury post-ischemia-reperfusion 13,37,38 . However, the precise mechanisms remain to be fully explored. ...
Purpose
Hypertrophic cardiomyopathy (HCM) is a prevalent condition posing a severe threat to human health. This study aims to investigate the expression of STAT3 in HCM and its potential mechanisms.
Methods
Two sets of data from hypertrophic cardiomyopathy patients and healthy individuals were downloaded from the Gene Expression Omnibus (GEO) database. After batch effect removal and merging, differential analysis of STAT3 between healthy individuals and HCM such as limma and Weighted correlation network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed for gene function enrichment. In vitro experiments involved constructing angiotensin II (Ang II)-induced H9c2 cardiomyocytes to validate STAT3 expression and explore the impact of hydrogen sulfide(H2S) intervention on improving drug targets for H9c2 cardiomyocyte hypertrophy. Lastly, MR was utilized to explore the causal relationship between STAT3 and HCM.
Results
STAT3 exhibited high expression in HCM patients. GO analysis indicated enrichment in immune responses, cell proliferation, and transcription. KEGG analysis suggested associations between HCM and pathways like JAK/STAT and NF-kβ. In vitro experiments demonstrated no significant change in STAT3 within Ang II-induced H9c2 cardiomyocytes, with an upregulation of P-STAT3 and hypertrophy-related proteins ANP and BNP. However, these changes were attenuated following H2S intervention. MR showed no causal relationship between STAT3 and HCM. In conclusion, while STAT3 may be associated with HCM occurrence, its expression doesn't exhibit a causal relationship with HCM. The mechanism for STAT3-induced HCM might be linked to increased P-STAT3 levels, and H2S might ameliorate HCM by inhibiting STAT3 phosphorylation.
... We found that dapagliflozin reduced the myocardial mRNA levels of BTB and CNC homology 1 (Bach1), a transcriptional repressor of antioxidative enzymes [71]. Myocardial Bach1 protein expression is increased in db/db mice relative to non-diabetic C57BLKS/J mice [32]. Seven days of exposure to exogenously administered antioxidant sodium sulfide reduced nuclear expression of Bach1 in the hearts of db/db diabetic mice with a resultant increase in heme oxygenase-1 (HO-1) expression [32]. ...
... Myocardial Bach1 protein expression is increased in db/db mice relative to non-diabetic C57BLKS/J mice [32]. Seven days of exposure to exogenously administered antioxidant sodium sulfide reduced nuclear expression of Bach1 in the hearts of db/db diabetic mice with a resultant increase in heme oxygenase-1 (HO-1) expression [32]. The effect of SGLT2 inhibition on Bach1 expression has not been reported, but the downstream gene HO-1 is increased by empagliflozin in the heart of diabetic KK-Ay mice, which is consistent with inhibition of Bach1 [33]. ...
Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved for the treatment of type 2 diabetes, heart failure, and chronic kidney disease. DAPA-HF and DELIVER trial results demonstrate that the cardiovascular protective effect of dapagliflozin extends to non-diabetic patients. Hence, the mechanism-of-action may extend beyond glucose-lowering and is not completely elucidated. We have previously shown that dapagliflozin reduces cardiac hypertrophy, inflammation, fibrosis, and apoptosis and increases ejection fraction in BTBR mice with type 2 diabetes.
We conducted a follow-up RNA-sequencing study on the heart tissue of these animals and performed differential expression and Ingenuity Pathway analysis. Selected markers were confirmed by RT-PCR and Western blot.
SGLT2 had negligible expression in heart tissue. Dapagliflozin improved cardiac metabolism by decreasing glycolysis and pyruvate utilization enzymes, induced antioxidant enzymes, and decreased expression of hypoxia markers. Expression of inflammation, apoptosis, and hypertrophy pathways was decreased. These observations corresponded to the effects of dapagliflozin in the clinical trials.
... H 2 S can also decrease pain sensation in the colon [161], and promotes healing [162] as well as resolution of colitis in preclinical animal trials [14,19,151,163]. Moreover, H 2 S protects mitochondria and their function in situations in which oxygen is low by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2) stress response pathway, which increases detoxifying proteins and antioxidants [164][165][166][167]. Endogenous H 2 S is also able to reduce inflammation by decreasing the production of pro-inflammatory cytokines and by modulating the frequency and number of granulocyte-like myeloid-derived suppressor cells [16]. ...
Hydrogen sulfide (H2S), originally known as toxic gas, has now attracted attention as one of the gasotransmitters involved in many reactions in the human body. H2S has been assumed to play a role in the pathogenesis of many chronic diseases, of which the exact pathogenesis remains unknown. One of them is inflammatory bowel disease (IBD), a chronic intestinal disease subclassified as Crohn’s disease (CD) and ulcerative colitis (UC). Any change in the amount of H2S seems to be linked to inflammation in this illness. These changes can be brought about by alterations in the microbiota, in the endogenous metabolism of H2S and in the diet. As both too little and too much H2S drive inflammation, a balanced level is needed for intestinal health. The aim of this review is to summarize the available literature published until June 2023 in order to provide an overview of the current knowledge of the connection between H2S and IBD.
... However, cartilage from both OA and OA-DB patients show an impairment in the expression of these H 2 S-synthesizing enzymes [4,46]. H 2 S levels are likewise reduced in DB and thus evidence suggest that this event could underlie DB pathogenesis and associated complications [44,61], likely due to the fact that endogenous level of the gas has been linked to macrophage activation and polarization, regulating the balance of M1/ M2-like macrophage by reducing M1 abundance in adipose tissue from DB patients [59,78]. ...
Type 2 diabetes (DB) is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Synovial macrophages from OA patients with DB present a marked pro-inflammatory phenotype. Since hydrogen sulphide (H2S) has been previously described to be involved in macrophage polarization, in this study we examined H2S biosynthesis in synovial tissue from OA patients with DB, observing a reduction of H2S-synthetizing enzymes in this subset of individuals. To elucidate these findings, we detected that differentiated TPH-1 cells to macrophages exposed to high levels of glucose presented a lower expression of H2S-synthetizing enzymes and an increased inflammatory response to LPS, showing upregulated expression of markers associated with M1 phenotype (i.e., CD11c, CD86, iNOS, and IL-6) and reduced levels of those related to M2 fate (CD206 and CD163). The co-treatment of the cells with a slow-releasing H2S donor, GYY-4137, attenuated the expression of M1 markers, but failed to modulate the levels of M2 indicators. GYY-4137 also reduced HIF-1α expression and upregulated the protein levels of HO-1, suggesting their involvement in the anti-inflammatory effects of H2S induction. In addition, we observed that intraarticular administration of H2S donor attenuated synovial abundance of CD68+ cells, mainly macrophages, in an in vivo model of OA. Taken together, the findings of this study seem to reinforce the key role of H2S in the M1-like polarization of synovial macrophages associated to OA and specifically its metabolic phenotype, opening new therapeutic perspectives in the management of this pathology.
... Similarly, NO therapy was found to increase the levels of H 2 S in murine HF model [9]. Endogenously produced H 2 S exerts a variety of cytoprotective actions in vivo, by acting as an antioxidant and promoting Nrf2 and NRF-1 signaling [10][11][12], and thereby augmenting NO-mediated signaling [4]. ...
Endogenously produced hydrogen sulfide (H2S) is critical for cardiovascular homeostasis. Therapeutic strategies aimed at increasing H2S levels have proven cardioprotective in models of acute myocardial infarction (MI) and heart failure (HF). The present study was undertaken to investigate the effects of a novel H2S prodrug, SG-1002, on stress induced hypertrophic signaling in murine HL-1 cardiac muscle cells. Treatment of HL-1 cells with SG-1002 under serum starvation without or with H2O2 increased the levels of H2S, H2S producing enzyme, and cystathionine β-synthase (CBS), as well as antioxidant protein levels, such as super oxide dismutase1 (SOD1) and catalase, and additionally decreased oxidative stress. SG-1002 also decreased the expression of hypertrophic/HF protein markers such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), galectin-3, TIMP1, collagen type III, and TGF-β1 in stressed HL-1 cells. Treatment with SG-1002 caused a significant induction of cell viability and a marked reduction of cellular cytotoxicity in HL-1 cells under serum starvation incubated without or with H2O2. Experimental results of this study suggest that SG-1002 attenuates myocardial cellular oxidative damage and/or hypertrophic signaling via increasing H2S levels or H2S producing enzymes, CBS, and antioxidant proteins.
... H2S pre-treatment could also be especially valuable in diabetes mellitus patients, who are at increased risk for myocardial ischemia and its associated mortality [70]. In db/db mice, the cardioprotective effect of H2S pre-treatment against myocardial IRI has been described [71]. Taken together, the cardioprotective effects of H2S pre-treatment in these experimental models demonstrate the need for further research on the potential of clinically viable H2S donor molecules in attenuating the damage induced by myocardial IRI. ...
Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies, such as static cold storage (SCS), are aimed at reducing IRI. However, prolonged SCS exacerbates IRI. Recent research has examined pre-treatment approaches to more effectively attenuate IRI. Hydrogen sulfide (H2S), the third established member of a family of gaseous signaling molecules, has been shown to target the pathophysiology of IRI and thus appears to be a viable candidate that can overcome the transplant surgeon’s enemy. This review discusses pre-treatment of renal grafts and other transplantable organs with H2S to mitigate transplantation-induced IRI in animal models of transplantation. In addition, ethical principles of pre-treatment and potential applications of H2S pre-treatment in the prevention of other IRI-associated conditions are discussed.
... Overexpression of Nrf2, or pharmacological activation using dh404, recovered insulin sensitivity and rescued glucose uptake in insulin-resistant cardiomyocytes (129). Hydrogen sulfide preconditioning has also been shown to reduce myocardial injury in db/db mice via upregulation of NRF2-mediated transcription of Nqo1 and Hmox1, which was associated with decreased Bach1 expression (130,131). Finally, muscle-specific overexpression of Nrf2 in db/db mice (db/db:Keap1 MuKo ) lowered blood glucose levels via increased glucose uptake into the skeletal muscle (132), and mice fed a high-fat diet supplemented with curcumin exhibited decreased muscular oxidative stress via upregulation of NRF2 (133). These studies indicate that NRF2 activation in the heart and skeletal muscle reduces oxidative stress and improves heart and muscle function in various genetic and dietary models of diabetes. ...
Despite decades of scientific effort, diabetes continues to represent an incredibly complex and difficult disease to treat. This is due in large part to the multifactorial nature of disease onset and progression and the multiple organ systems affected. An increasing body of scientific evidence indicates that a key mediator of diabetes progression is NRF2, a critical transcription factor that regulates redox, protein, and metabolic homeostasis. Importantly, while experimental studies have confirmed the critical nature of proper NRF2 function in preventing the onset of diabetic outcomes, we have only just begun to scratch the surface of understanding the mechanisms by which NRF2 modulates diabetes progression, particularly across different causative contexts. One reason for this is the contradictory nature of the current literature, which can often be accredited to model discrepancies, as well as whether NRF2 is activated in an acute or chronic manner. Furthermore, despite therapeutic promise, there are no current NRF2 activators in clinical trials for the treatment of patients with diabetes. In this review, we briefly introduce the transcriptional programs regulated by NRF2 as well as how NRF2 itself is regulated. We also review the current literature regarding NRF2 modulation of diabetic phenotypes across the different diabetes subtypes, including a brief discussion of contradictory results, as well as what is needed to progress the NRF2 diabetes field forward.
