| Popis: |
Calcium (Ca2+) overload and oxidative stress are major pathological mechanisms underlying cardiac injury and arrhythmogenesis during myocardial ischemia and reperfusion. Stromal interaction molecule 1 (STIM1) regulates store-operated Ca2+ entry (SOCE) in cardiomyocytes. Upon Ca2+ depletion in sarcoplasmic reticulum, STIM1 activates Ca2+-release-activated channel (CRAC) to mediate SOCE. Excessive or insufficient SOCE activities increase the risk of cardiac arrhythmias. STIM1 Cys56/49Ala double mutation decreases SOCE activation while oxidant-induced S-glutathionylation of Cys56 upregulates SOCE. This thesis tested the hypothesis that STIM1 Cys56Ser or Cys49Ser mutation leads to SOCE dysregulation and enhances cardiac arrhythmia in myocardial I/R injury. The results show that STIM1 Cys56Ser or Cys49Ser mutant mice exhibited a significantly higher incidence of cardiac arrhythmias than WT mice during myocardial I/R. In STIM1 mutant cardiomyocytes, basal SOCE activities were reduced while H2O2 stimulated SOCE activities were enhanced. Collectively, these data show important physiological roles of STIM1 Cys49 and Cys56 in regulating SOCE activity and protecting the heart from cardiac arrhythmia during myocardial I/R. |
