Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein-protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

• MeSH
• chinoxaliny aplikace a dávkování   farmakologie   MeSH
• glykolýza MeSH
• mapy interakcí proteinů MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• oxidativní fosforylace MeSH
• proteomika metody   MeSH
• receptor pro glukagonu podobný peptid 1 agonisté   MeSH
• remodelace komor účinky léků   MeSH
• sarkoplazmatická Ca2+-ATPáza metabolismus   MeSH
• srdeční komory metabolismus   MeSH
• srdeční mitochondrie metabolismus   MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The effects of ER stress on protein secretion by cardiac myocytes are not well understood. In this study, the ER stressor thapsigargin (TG), which depletes ER calcium, induced death of cultured neonatal rat ventricular myocytes (NRVMs) in high media volume but fostered protection in low media volume. In contrast, another ER stressor, tunicamycin (TM), a protein glycosylation inhibitor, induced NRVM death in all media volumes, suggesting that protective proteins were secreted in response to TG but not TM. Proteomic analyses of TG- and TM-conditioned media showed that the secretion of most proteins was inhibited by TG and TM; however, secretion of several ER-resident proteins, including GRP78 was increased by TG but not TM. Simulated ischemia, which decreases ER/SR calcium also increased secretion of these proteins. Mechanistically, secreted GRP78 was shown to enhance survival of NRVMs by collaborating with a cell-surface protein, CRIPTO, to activate protective AKT signaling and to inhibit death-promoting SMAD2 signaling. Thus, proteins secreted during ER stress mediated by ER calcium depletion can enhance cardiac myocyte viability.

• MeSH
• apoptóza MeSH
• autokrinní signalizace MeSH
• biologické markery MeSH
• epidermální růstový faktor metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• membránové glykoproteiny metabolismus   MeSH
• myši MeSH
• náchylnost k nemoci MeSH
• nádorové proteiny metabolismus   MeSH
• parakrinní signalizace MeSH
• proteom * MeSH
• proteomika * metody   MeSH
• sarkoplazmatické retikulum metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• stres endoplazmatického retikula * účinky léků   MeSH
• thapsigargin farmakologie   MeSH
• vápník metabolismus   MeSH
• vápníková signalizace účinky léků   MeSH
• viabilita buněk MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH