Abstract
Hydrogen sulfide (H2S) is protective in myocardial ischemia/reperfusion injury (I/R). However, venous injection of NaHS and local injection of adenovirus with cystathionine-γ-lyase (CSE) plasmids was used to increase H2S concentration presented low-efficiency and side-effect. In this study, we explored a cardiac-specific approach to increase the local expression of H2S, the efficacy in I/R, and the underlying mechanism. Angiotensin 1 (AT1) conjugated nanocarrier (CdSe/ZnS quantum dots) carrying cystathionine-γ-lyase (CSE) plasmid targeted myocardium was constructed and injected intravenously into the I/R animal model. The nanocarrier location was confirmed. The expression levels of CSE in different organs was also compared. The efficacy of nanocarrier was investigated in vivo and in vitro. In vivo fluorescence imaging system showed that the nanocarrier mostly enriched in the heart. Western blot demonstrated that CSE expression in the heart was higher in the AT1 group than the control group. There was no difference in other organs. Experiments in vitro showed that the nanocarrier had a high transfection efficiency. The CSE expression was also increased in the CSE group than the vector group. The IR rat was injected with the nanocarrier which decreased the infarct size and increased the ejection fraction. Cell viability and LDH concentration were also reduced in vitro at the same time. Key markers of endoplasmic reticulum stress (ERS) including CHOP, GRP78, eIF2a expression level and mitophagy (Parkin, NIX, ATG) were all decreased in the CSE group. The rat was injected with an adenovirus vector carrying the CHOP gene which reversed the reduced mitophagy by CSE. In summary, the nanocarrier carrying CSE plasmid targeted myocardium with AT1 peptide can reduce the I/R without affecting other tissue. It inhibits ERS and mitophagy via the CHOP/GRP78/eIF2a signaling pathway.
Endothelial Dysfunction of Bypass Graft: Direct Comparison of In Vitro and In Vivo Models of Ischemia-Reperfusion Injury
