Polycystin-2 is cardioprotective against myocardial infarction by regulating the calcium-mediated ER stress response.

Abstract

BackgroundPatients with autosomal polycystic kidney disease (ADPKD) have an increased risk and worsened outcomes for acute myocardial infarction (AMI), but the mechanism behind this is unknown. Polycystin 2 (PC2), the protein encoded by one of the two main genes mutated in ADPKD, is a calcium-permeant channel ubiquitously expressed; however, its role in cardiomyocytes remains poorly understood. One hallmark of AMI is ER stress, which PC2 is known to regulate adaptively; however, whether PC2 regulates ER stress in the ischemic heart is unknown. ObjectiveThis study investigates the mechanism by which PC2 regulates ER stress in myocardial ischemia. Methods and ResultsPC2 protein was increased in human ischemic heart failure samples and murine myocardial infarct samples, and it was enriched at ER-mitochondrial contact sites. Induction of myocardial infarction (MI) in cardiomyocyte-specific PC2-KO mice led to cardiac dysfunction and reduced PERK expression compared to control MI mice. ER stress induced by tunicamycin in vitro blunted PERK phosphorylation and subsequent CHOP upregulation in PC2 KO cells. Tunicamycin-induced ER stress resulted in a PC2-dependent ER calcium leak and mitochondrial calcium transients, along with increased mitochondrial function, all of which were decreased in PC2 KO cells. Moreover, PC2 KO cells after ER stress exhibited decreased mitochondrial membrane potential and increased apoptosis. Isolated WT cardiomyocytes exhibited increased diastolic calcium after acute ER stress induction and increased mitochondrial uptake, neither of which was seen in PC2 KO cells. Re-expression of full-length PC2 in vitro restored both the calcium leak and PERK phosphorylation in PC2 KO cells under ER stress, but not a pathological mutant PC2 D511V, which impairs ion channel activity. ConclusionsPC2 is upregulated during ER stress, where it localizes at ER-mitochondrial contact sites and acts as an ER calcium leak channel, thereby restoring cellular homeostasis during the adaptive phase of ER stress. PC2 provides cardioprotection during ischemic events by preventing maladaptive ER stress, which contributes to cardiac dysfunction. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/668747v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1e416d5org.highwire.dtl.DTLVardef@1971fd9org.highwire.dtl.DTLVardef@abeebcorg.highwire.dtl.DTLVardef@1c68f8d_HPS_FORMAT_FIGEXP M_FIG C_FIG