Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca2+/calmodulin-dependent protein kinaseⅡ

Dan WU,Qing-xun HU,De-qiu ZHU,Yi-zhun ZHU

(1.Department of Pharmacy,Tongji Hospital,Tongji University School of Medicine,Shanghai 200065,China;2.School of Pharmacy,Macau University of Science and Technology,Macau,China;3.Mitochondria and Metabolism Center,Department of Anesthesiology&Pain Medicine,University of Washington,Seattle,WA 98109,USA）

T3-16

Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca2+/calmodulin-dependent protein kinaseⅡ

Dan WU1,Qing-xun HU3,De-qiu ZHU1,Yi-zhun ZHU2

(1.Department of Pharmacy,Tongji Hospital,Tongji University School of Medicine,Shanghai 200065,China;2.School of Pharmacy,Macau University of Science and Technology,Macau,China;3.Mitochondria and Metabolism Center,Department of Anesthesiology&Pain Medicine,University of Washington,Seattle,WA 98109,USA）

OBJECTIVETo determine the functional role of hydrogen sulfide(H2S)in protecting against mitochondrial dysfunction in heart failure through the inhibition of Ca2+/calmodulin-dependent protein kinaseⅡ (CaMKⅡ)using wild type and CSE knockout mouse models.METHODSContinuous subcutaneous injection isoprenaline(7.5 mg·kg-1·d-1),once a day for 4 weeks to induce heart failure in Male C57BL/6(6-8 weeks old)mice and CSE-/-mice.150 μmol·L-1H2O2was used to induce oxidative stress in H9c2 cells.Echocardiograph was used to detect cardiac parameters.H&E stain and Masson stain was to observation histopathological changes.Western blot was used to detect protein expression and activity.The siRNA was used to silence protein expression.HPLC was used to detect H2S level.Biotin assay was used to detect the level of S-sulfhydration protein.RESULTSTreatment with S-propyl-L-cysteine(SPRC)or sodium hydrosulfide(NaHS),modulators of blood H2S levels,attenuated the development of heart failure in animals,reduced lipid peroxidation,and preserved mitochondrial function.The inhibition CaMKⅡphosphorylation by SPRC and NaHS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds.Interestingly,CaMKⅡactivity was found to be elevated in CSE-/-mice as compared to wild type animals and the phosphorylation status of CaMKⅡappeared to relate to the severity of heart failure.Importantly,in wild type mice SPRC was found to promote S-sulfhydration of CaMKII leading to reduced activity of this protein however,in CSE-/-mice S-sulfhydration was abolished following SPRC treatment.CONCLUSIONA novel mechanism depicting a role of S-sulfhydration in the regulation of CaMKⅡis presented.SPRC mediated S-sulfhydration of CaMKII was found to inhibit CaMKⅡactivity and to preserve cardiovascular homeostasis.

hydrogen sulfide;mitochondria;heart failure;Ca2+/calmodulin-dependent protein kinaseⅡ;S-sulfhydration

Yi-zhun ZHU,Tel:（0853)88972880,E-mail：yzzhu@must.edu.mo