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Hydrogen Sulfide Ameliorates Homocysteine-Induced Cardiac Remodeling and Dysfunction.

ABSTRACT: Patients with diabetes, a methionine-rich meat diet, or certain genetic polymorphisms show elevated levels of homocysteine (Hcy), which is strongly associated with the development of cardiovascular disease including diabetic cardiomyopathy. However, reducing Hcy levels with folate shows no beneficial cardiac effects. We have previously shown that a hydrogen sulfide (H2S), a by-product of Hcy through transsulfuration by cystathionine beta synthase (CBS), donor mitigates Hcy-induced hypertrophy in cardiomyocytes. However, the in vivo cardiac effects of H2S in the context of hyperhomocysteinemia (HHcy) have not been studied. We tested the hypothesis that HHcy causes cardiac remodeling and dysfunction in vivo, which is ameliorated by H2S. Twelve-week-old male CBS+/- (a model of HHcy) and sibling CBS+/+ (WT) mice were treated with SG1002 (a slow release H2S donor) diet for 4 months. The left ventricle of CBS+/- mice showed increased expression of early remodeling signals c-Jun and c-Fos, increased interstitial collagen deposition, and increased cellular hypertrophy. Notably, SG1002 treatment slightly reduced c-Jun and c-Fos expression, decreased interstitial fibrosis, and reduced cellular hypertrophy. Pressure volume loop analyses in CBS+/- mice revealed increased end systolic pressure with no change in stroke volume (SV) suggesting increased afterload, which was abolished by SG1002 treatment. Additionally, SG1002 treatment increased end-diastolic volume and SV in CBS+/- mice, suggesting increased ventricular filling. These results demonstrate SG1002 treatment alleviates cardiac remodeling and afterload in HHcy mice. H2S may be cardioprotective in conditions where H2S is reduced and Hcy is elevated.

SUBMITTER: Kar S

PROVIDER: S-EPMC6544124 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Hydrogen Sulfide Ameliorates Homocysteine-Induced Cardiac Remodeling and Dysfunction.

Kar Sumit S Shahshahan Hamid R HR Kambis Tyler N TN Yadav Santosh K SK Li Zhen Z Lefer David J DJ Mishra Paras K PK

Frontiers in physiology 20190524

Patients with diabetes, a methionine-rich meat diet, or certain genetic polymorphisms show elevated levels of homocysteine (Hcy), which is strongly associated with the development of cardiovascular disease including diabetic cardiomyopathy. However, reducing Hcy levels with folate shows no beneficial cardiac effects. We have previously shown that a hydrogen sulfide (H<sub>2</sub>S), a by-product of Hcy through transsulfuration by cystathionine beta synthase (CBS), donor mitigates Hcy-induced hyp ...[more]

PMID: 31178749

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Project description:The mutual interactions between reactive oxygen species, airway inflammation, and alveolar cell death play crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). In the present study, we investigated the possibility that hydrogen sulfide (H(2)S) donor sodium hydrosulfide (NaHS) might be a novel option for intervention in COPD.We used a mouse model of tobacco smoke (TS)-induced emphysema. Mice were injected with H(2)S donor NaHS (50 ?mol/kg in 0.25 ml phosphate buffer saline, intraperitoneally) or vehicle daily before exposed to TS for 1 h/day, 5 days/week for 12 and 24 weeks. We found that NaHS ameliorated TS-induced increase in mean linear intercepts, the thickness of bronchial walls, and the numbers of total cell counts as well as neutrophils, monocytes, and tumor necrosis factor ? in bronchial alveolar lavage. Moreover, NaHS reduced increases in right ventricular systolic pressure, the thickness of pulmonary vascular walls, and the ratio of RV/LV+S in TS-exposed mice. Further, TS exposure for 12 and 24 weeks reduced the protein contents of cystathionine ?-lyase (CGL), cystathionine ?-synthetase (CBS), nuclear erythroid-related factor 2 (Nrf2), P(ser473)-Akt, as well as glutathione/oxidized glutathione ratio in the lungs. TS-exposed lungs exhibited large amounts of 8-hydroxyguanine-positive and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Treatment with NaHS increased P(ser473)-Akt and attenuated TS-induced reduction of CGL, CBS, and Nrf2 as well as glutathione/oxidized glutathione ratio in the lungs. NaHS also reduced amounts of 8-hydroxyguanine-positive, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and active caspase-3 in TS-exposed lungs. Additionally, knocking-down Akt protein abolished the protective effects of NaHS against TS-induced apoptosis and downregulation of Nrf2, CGL, and CBS in pulmonary artery endothelial cells.These results indicate that NaHS protects against TS-induced oxidative stress, airway inflammation, and remodeling and ameliorates the development of emphysema and pulmonary hypertension. H(2)S donors have therapeutic potential for the prevention and treatment of COPD caused by TS.

Dataset Information

Hydrogen Sulfide Ameliorates Homocysteine-Induced Cardiac Remodeling and Dysfunction.

Publications

Hydrogen Sulfide Ameliorates Homocysteine-Induced Cardiac Remodeling and Dysfunction.

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