کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8474764 | 1550431 | 2014 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia/reperfusion injury
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کلمات کلیدی
PLNRyR2pKaCaMKIIGAPDHTTCSERCA2aCa2+ - Ca2 +I/R - I / RIschemia/reperfusion injury - آسیب شناسی ایسکمی / رپرفیوژنMyocardial infarction - آنفارکتوس میوکاردischemia/reperfusion - ایسکمی / رپرفیوژنthreonine - ترئونینTriphenyltetrazolium chloride - ترفتhenyltetrazolium chlorideTUNEL - تونلApoptosis - خزان یاختهایSarcoplasmic reticulum - رتیکولوم سارکوپلاسمیکSerine - سرینphospholamban - فسفولامبنLAD - لادوLDH - لاکتات دهیدروژناز به صورت مختصر شده LDH terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling - مارک نهایی با نام dUTP تخصیص داده شده توسط ترمینال deoxynucleotidyl transferase استMyocardium - میوکارد wild-type - نوع وحشیNecrosis - نکروز یا بافتمردگیprotein kinase A - پروتئین کیناز Aleft anterior descending - چپ قدامی نزولیCalcium - کلسیمglyceraldehyde 3-phosphate dehydrogenase - گلیسرولیدید 3-فسفات دهیدروژناز
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Ca2+-calmodulin kinase II (CaMKII) activation is deleterious in cardiac ischemia/reperfusion (I/R). Moreover, inhibition of CaMKII-dependent phosphorylations at the sarcoplasmic reticulum (SR) prevents CaMKII-induced I/R damage. However, the downstream targets of CaMKII at the SR level, responsible for this detrimental effect, remain unclear. In the present study we aimed to dissect the role of the two main substrates of CaMKII at the SR level, phospholamban (PLN) and ryanodine receptors (RyR2), in CaMKII-dependent I/R injury. In mouse hearts subjected to global I/R (45/120Â min), phosphorylation of the primary CaMKII sites, S2814 on cardiac RyR2 and of T17 on PLN, significantly increased at the onset of reperfusion whereas PKA-dependent phosphorylation of RyR2 and PLN did not change. Similar results were obtained in vivo, in mice subjected to regional myocardial I/R (1/24Â h). Knock-in mice with an inactivated serine 2814 phosphorylation site on RyR2 (S2814A) significantly improved post-ischemic mechanical recovery, reduced infarct size and decreased apoptosis. Conversely, knock-in mice, in which CaMKII site of RyR2 is constitutively activated (S2814D), significantly increased infarct size and exacerbated apoptosis. In S2814A and S2814D mice subjected to regional myocardial ischemia, infarct size was also decreased and increased respectively. Transgenic mice with double-mutant non-phosphorylatable PLN (S16A/T17A) in the PLN knockout background (PLNDM) also showed significantly increased post-ischemic cardiac damage. This effect cannot be attributed to PKA-dependent PLN phosphorylation and was not due to the enhanced L-type Ca2+ current, present in these mice. Our results reveal a major role for the phosphorylation of S2814 site on RyR2 in CaMKII-dependent I/R cardiac damage. In contrast, they showed that CaMKII-dependent increase in PLN phosphorylation during reperfusion opposes rather than contributes to I/R damage.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 74, September 2014, Pages 274-283
Journal: Journal of Molecular and Cellular Cardiology - Volume 74, September 2014, Pages 274-283
نویسندگان
Mariano N. Di Carlo, Matilde Said, Haiyun Ling, Carlos A. Valverde, Verónica C. De Giusti, Leandro Sommese, Julieta Palomeque, Ernesto A. Aiello, Darlene G. Skapura, Gustavo Rinaldi, Jonathan L. Respress, Joan Heller Brown, Xander H.T. Wehrens,