Oxidative stress-induced leaky sarcoplasmic reticulum underlying acute heart failure in severe burn trauma

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 RyRʹs from oxidative stress-induced hypersensitivity.