Abstract
Stress cardiomyopathy is a major clinical complication after severe burn. Multiple upstream initiators have been identified; however, the downstream targets are not fully understood. This study assessed the role of the plasma membrane in this process and its relationship with the protease μ-calpain and tumor necrosis factor-alpha (TNF-α). Here, third-degree burn injury of approximately 40% of the total body surface area was established in rats. Plasma levels of LDH and cTnI and cardiac cell apoptosis increased at 0.5 h post burn, reached a peak at 6 h, and gradually declined at 24 h. This effect correlated well with not only the disruption of cytoskeletal proteins, including dystrophin and ankyrin-B, but also with the activation of μ-calpain, as indicated by the cleaved fragments of α-spectrin and membrane recruitment of the catalytic subunit CAPN1. More importantly, these alterations were diminished by blocking calpain activity with MDL28170. Burn injury markedly increased the cellular uptake of Evans blue, indicating membrane integrity disruption, and this effect was also reversed by MDL28170. Compared with those in the control group, cardiac cells in the burn plasma-treated group were more prone to damage, as indicated by a marked decrease in cell viability and increases in LDH release and apoptosis. Of note, these alterations were mitigated by CAPN1 siRNA. Moreover, after neutralizing TNF-α with rhTNFR:Fc, calpain activity was blocked, and heart function was improved. In conclusion, we identified μ-calpain as a trigger for severe burn-induced membrane disruption in the heart and provided evidence for the application of rhTNFR:Fc to inhibit calpain for cardioprotection.
Highlights
Stress cardiomyopathy or cardiac dysfunction is a major clinical complication of severe burns [1, 2]
Stress cardiomyopathy is characterized by impaired cardiac output, decreased mean arterial pressure, increased plasma levels of the lactate dehydrogenase (LDH) and cardiac troponin I, and cardiac cell death in clinical and animal studies [3, 4]
The DNA repair enzyme PARP-1, which is 116 kDa, was apparently cleaved into fragments (89 kDa), indicating the occurrence of apoptosis (Fig. 1B), there was no discerned cleavage of full-length GSDME, which is an indicator of pyroptosis (Fig. 1B)
Summary
Stress cardiomyopathy or cardiac dysfunction is a major clinical complication of severe burns [1, 2]. Some of the identified upstream initiators include (1) reduced venous return due to microvascular hyperpermeability and a 10- to 20-fold surge in plasma catecholamines, leading to hypovolemic perfusion and an increase in oxygen consumption in the heart [3]; (2) systemic proinflammatory mediator storms, including tumor necrosis factor-α, interleukin1β, and interleukin-6, which alone or in concert, depress heart function and induce cell death [6]; and (3) bioenergetic perturbations due to insulin resistance and mitochondrial dysfunction, which predispose cardiac cells to hypoxic insult [7, 8].
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