Cardiac Ionotropic Glutamate Receptor Function

Glutamate is the most important excitatory neurotransmitter in central nervous systemand is responsible for mediating a broad range of physiological or pathological responses.Glutamate receptors can be cataloged into two groups: metabotropic receptors (mGluRs, Gprotein-coupled receptors) and ionotropic receptors (iGluRs, ligand-gated channels). TheiGluRs are subclassified into three subtypes according to their most selective agonists:N-methyl-D-asparttate receptor (NMDA-R),α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPA-R) and kainate receptor (KA-R). At present, most ofstudies have been focused on the central nervous system, although GluRs have beenidentified in most peripheral tissues, for example, in pancreas, lung, taste bud,keratinocytes, cochlea and heart. However, the role of GluRs on peripheral tissues,especially heart, is unclear. We have found in a preliminary study that iGluRs expression isupregulated in rats with cardiac nerve sprouting or chronic infarction. This finding suggeststhat iGluRs may have important role in the pathogenesis of arrhythmia and sudden death inchronic myocardial infarction.Sudden cardiac death (SCD) refers to sudden and unexpected death caused bycardiac diseases, which is often the result of life-threatening arrhythmias such asventricular fibrillation (VF). SCD occurs mainly among patients with coronary arterydiseases, especially in those with myocardial infarction (MI). The mechanism of SCD isnot fully understood. One important hypothesis is that increased symspathetic tone may bea trigger of VF and SCD. Cao et al reported that sympathetic nerve sprouting andremodeling are responsible for the pathogenesis of VF and SCD in chronic MI. However,the linker between nerve sprouting and arrhythmia is still unclear. We hypothesize thatiGluRs may take the role.The present study focused on the cardiac function of iGluRs, especially the role ofiGluRs in relating cardiac nerve sprouting and arrhythmia by using in vivo model and cellcultures. We also investigated the effect of excitation of iGluRs on myocardial generation of oxygen species, mitochondrial function and apoptosis.In the first part of the study, we established a rat model of cardiac sympathetic nervesprouting by subcutaneously injecting 4-Methylcatechol (4-MC), a strong stimulator ofendogeneous NGF synthesis, to induce cardaic nerve sprouting. We found that themyocardial expression of NMDA-R and AMPA-R were significantly upregulated in ratswith cardiac nerve sprouting or MI. A combination of nerve sprouting and MI furtherupregulated the expression of NMDA-R and AMPA-R. We also found that apoptoticcardiomyocytes were significantly increased in rats with cardiac nerve sprouting or MI.Based on these findings, we further investigated the role of iGluR excitation oncardiomyoctes. The results showed that NMDA receptor activation induced apoptosis incardiomyocytes. We further identified that the apoptosis of cardiomyocytes was inducedthrough Ca²⁺ overload, the generation of reactive oxygen species, the decrease ofmitochondrial membrane potential (Δ(?)m) and thereafter the release of cytochrome c intocysole, the upregulation of Bax and downregulation of Bcl-2, and finally the activation ofcaspase-3. AMPA could also induce apoptosis of cardiomyocytes when it's rapiddesensitization was blocked by CYZ. We further found that mitochondria membranepotential was not involved in the pathogenesis of apoptosis induced by AMPA.Taken together, we conclude that iGluRs play a negative role on the heart functionand rhythm in rats with sympathetic nerve sprouting or MI. The upregulationof theexpression of iGluRs in cardiac nerve sprouting or MI may cause a higher sensitivity toglutamate and therefore lead to the glutamate cardiotoxicity, including calcium overload,oxidative cell damage, mitochondrial disfunction and apoptosis. When there events occur,heart pumping function and electrophysiology may be disturbed, leading to arrhythmia andsudden cardiac death (SCD). Therefore, Glu-iGluRs signaling pathway may be taken as arisk factor in the pathogenesis of SCD. Inhibition of this signaling pathway may havepotential clinical perspectives in preventing SCD.