Abstract 1284: The Calmodulin Kinase II (CaMKII)-p38 MAPK-ATF6 Pathway Is Involved in the Endoplasmic Reticulum (ER) Stress and Myocyte Apoptosis in β1-Adrenergic Receptor (AR) Peptide Induced Cardiomyopathy
Objectives We sought to determine if the development of ER stress and myocyte apoptosis is mediated via activation of the CaMKII-p38 MAPK-ATF6 pathway in β1-AR peptide induced cardiomyopathy.
Background A synthetic 26-mer peptide (1 mg monthly) corresponding to the second extracellular loop of human β1-AR has been used to produce cardiac dysfunction and myocyte apoptosis in rabbits. We found that the cardiomyopathy is associated with ER stress and caspase-12-related apoptosis. To study whether β1AR antibody exerts its effects via its agonistic action on the β-AR, we compared the effects of β1AR immunization with NE, and investigated whether the cardiomyopathy was caused by the β1AR-mediated activation of the CaMKII, p38 MAPK and ATF6 pathway.
Methods Four groups of rabbits were studied: 1) β1AR peptide immunization (n=16), 2) Control Freund’s adjuvant treatment (n=11), 3) NE infusion (50 mg 90-day release pellet, n=7) and 4) NE plus β1AR peptide immunization (n=16) for 6 months. Hemodynamics, echocardiograms and serum anti-β1AR antibody titers (ELISA) were measured monthly. At Month 6, animals were sacrificed, and the hearts removed for measuring cardiomyocyte apoptosis (TUNEL), cleavage of procaspase-12, CaMKII activity, phosphorylation of p38MAPK and cleavage of ATF6 (Western).
Results β1AR immunization produced a dilated cardiomyopathy. This was associated with an increase of TUNEL positive cells, breakdown of procaspase-12, increased CaMKII activity, phosphorylation of p38 MAPK and cleavage of ATF6 to 36 kDa and 54 kDa fragments. Chronic NE produced similar changes in the CaMKII-p38 MAPK-ATF6 pathway, ER stress and cell apoptosis. Chronic administration of NE to peptide-immunized rabbits produced additive effects.
Conclusion Our findings suggest that the cardiomyopathy induced by β1AR peptide is mediated by the β-AR-agonistic effect of anti β1AR antibody, and that elevated plasma NE exaggerates the damage produced by β1AR peptide immunization.