Presenilin Mediated Ca2+ Changes and Protein Quality Control in Heart Failure

Idiopathic dilated cardiomyopathy (iDCM) is characterized by marked dysregulation of Ca2+ cycling with increased intracellular Ca2+ and decreased sarcoplasmic reticulum (SR) Ca2+. However,SR is also the site of protein synthesis and folding. Alterations of the quality of proteins have been identified in iDCM and genetic variants of presenilin 2 (PSEN2), a component of γ-secretase complex, were described in familial and sporadic cases of iDCM. We analyzed if the cellular response to ER stress, the unfolded protein response (UPR), is activated in iDCM where Ca2+ homeostasis is known to occur; we then evaluated if and how changes in PSEN2 affect ER Ca2+ homeostasis and UPR. In tissue extracts from 9 explanted iDCM and 7 non-failing donor hearts we evaluated the protein expression and RNA level of the UPR. iDCM hearts showed an increase in the expression of all ER chaperones tested indicating an overall activation of the ER stress response. KO mice for PSEN2 showed a dilated phenotype compared to WT (LVEDD p= 0.002; SW wall thickness p= 0.002; EF p=0.005). PSEN2 KO isolated myocytes showed 20% reduction in cell shortening at baseline. Following thapsigargin infusion to test the SR Ca2+ content, cells showed a 50% reduction in cell shortening and shortening velocity, 80% reduction in all diastolic velocity parameters, 25% and 60% increase in systolic and diastolic Ca2+ respectively. In the heart of PSEN2 KO mice, we showed a decrease in the expression of L-type Ca2+ channels, Ryanodine Receptor and the pentameric and monomeric phospholamban as well as the UPR proteins suggesting that changes in the expression of EC coupling lead to increased SR Ca2+ that may inactivate the UPR. PSEN2 plays a role in Ca2+ homeostasis and its loss leads to an increased sequestration of Ca2+ in the SR, contractile dysfunction and inactivation of the UPR. It is possible that over time misfolded proteins accumulate, activating the UPR, further impairing cardiac function. In conclusion, we described for the first time a chronic activation of the UPR in human iDCM induced and/or further sustained by the SR Ca2+ disequilibrium. Mice models of PSEN2 KO showed that PSEN2 plays a role in the cardiac function and ER Ca2+ cycling. Changes in protein quality control in the heart may be secondary to the changes in Ca2+ homeostasis.