Hydrogen Sulfide Treatment Improves Post-Infarct Remodeling and Long-Term Cardiac Function in CSE Knockout and Wild-Type Mice
2020
Leigh J. Ellmers | Evelyn M. Templeton | Anna P. Pilbrow | Chris Frampton | Isao Ishii | Philip K. Moore | Madhav Bhatia | A. Mark Richards | Vicky A. Cameron
Hydrogen sulfide (H<sub>2</sub>S) is recognized as an endogenous gaseous signaling molecule generated by cystathionine γ-lyase (CSE) in cardiovascular tissues. H<sub>2</sub>S up-regulation has been shown to reduce ischemic injury, and H<sub>2</sub>S donors are cardioprotective in rodent models when administered concurrent with myocardial ischemia. We evaluated the potential utility of H<sub>2</sub>S therapy in ameliorating cardiac remodeling with administration delayed until 2 h post-infarction in mice with or without cystathionine γ-lyase gene deletion (CSE<sup>–/–</sup>). The slow-release H<sub>2</sub>S donor, GYY4137, was administered from 2 h after surgery and daily for 28 days following myocardial infarction (MI) induced by coronary artery ligation, comparing responses in CSE<sup>–/–</sup> with wild-type (WT) mice (n = 5–10/group/genotype). Measures of cardiac function and expression of key genes associated with cardiac hypertrophy, fibrosis, and apoptosis were documented in atria, ventricle, and kidney tissues. Post-MI GYY4137 administration reduced infarct area and restored cardiac function, accompanied by reduction of the elevated ventricular expression of genes mediating cardiac remodeling to near-normal levels. Few differences between WT and CSE<sup>–/–</sup> mice were observed, except CSE<sup>–/–</sup> mice had higher blood pressures, and higher atrial Mir21a expression across all treatment groups. These findings suggest endogenous CSE gene deletion does not substantially exacerbate the long-term response to MI. Moreover, the H<sub>2</sub>S donor GYY4137 administered after onset of MI preserves cardiac function and protects against adverse cardiac remodeling in both WT and CSE-deficient mice.
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