Myocardial SERCA2 Protects Against Cardiac Damage and Dysfunction Caused by Inhaled Bromine

Abstract

Myocardial sarcoendoplasmic reticulum calcium ATPase 2 (SERCA2) activity is critical for heart function. We have demonstrated that inhaled halogen (chlorine or bromine) gases inactivate SERCA2, impair calcium homeostasis, increase proteolysis, and damage the myocardium ultimately leading to cardiac dysfunction. To further elucidate the mechanistic role of SERCA2 in halogen induced myocardial damage we utilized bromine exposed cardiac specific SERCA2 knockout (KO) mice (tamoxifen administered SERCA2(flox/flox) Tg(MHC-MerCreMer) mice) and compared them to the oil administered controls (FF). We performed echocardiography and hemodynamic analysis to investigate cardiac function 24h after bromine (600 ppm, for 30 min) exposure and measured cardiac injury markers in plasma, proteolytic activity in cardiac tissue and performed electron microscopy of the left ventricle (LV). Cardiac specific SERCA2 knockout mice demonstrated enhanced toxicity to bromine. Bromine exposure increased ultrastructural damage, perturbed LV shape geometry, and demonstrated acutely increased phosphorylation of phospholamban in the KO mice. Bromine exposed KO mice revealed significantly enhanced mean arterial pressure (MAP) and sphericity index, decreased LV end diastolic diameter LVEDD and LV end systolic pressure (LVESP), when compared to the bromine exposed control FF mice. Strain analysis showed loss of synchronicity, evidenced by an irregular endocardial shape in systole and irregular vector orientation of contractile motion across different segments of the LV in KO mice, both at baseline and after bromine exposure. These studies underscore the critical role of myocardial SERCA2 in preserving cardiac ultrastructure and function during toxic halogen gas exposures.