کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1911116 | 1046802 | 2008 | 11 صفحه PDF | دانلود رایگان |
Burn trauma causes cardiac dysfunction. However, much of the underlying cellular and molecular mechanisms remain elusive. In the present study, we demonstrate the roles of excessive sarcoplasmic reticulum (SR) Ca2+ leakage and oxidative stress in burn-associated acute heart failure. In cardiomyocytes from failing rat hearts 12 h after full-thickness cutaneous burn of about 40% of the total body surface area, we found that Ca2+ transients and contractility were impaired, but the triggering L-type Ca2+ channel current density was unaltered, giving rise to a significantly reduced gain of excitation–contraction coupling. This deficiency in SR Ca2+ release was accompanied by a reduction in Ca2+ content in the SR. Surprisingly, the frequency of spontaneous Ca2+ sparks was increased by 1.4-fold; Ca2+ tolerance test (10 mM extracellular Ca2+) further showed 2.0- and 1.5-fold more frequent Ca2+ waves and Ca2+ sparks, respectively. Myofilament sensitivity to Ca2+, however, seemed to be unaffected. These results suggest hyperactivity of the ryanodine receptor (RyR) Ca2+ release channel and a leaky SR in burn. Importantly, pretreatment with antioxidant vitamins C and E seemed to prevent burn-induced RyR hypersensitivity and SR leakage and thereby normalize Ca2+ transients and contractility. Concomitantly, the in vivo cardiac functions were also more tolerant of traumatic burn. Collectively, our findings suggest that SR leakage due to oxidative stress is likely a major candidate mechanism underlying burn-associated acute heart failure. Antioxidant therapy in burn trauma provides cardioprotection, at least in part, by protecting RyR's from oxidative stress-induced hypersensitivity.
Journal: Free Radical Biology and Medicine - Volume 44, Issue 3, 1 February 2008, Pages 375–385