Sergienko, Nicola M.Donner, Daniel G.Delbridge, Lea M. D.McMullen, Julie R....
15页
查看更多>>摘要：Protein phosphatases have emerged as critical regulators of phosphoprotein homeostasis in settings of health and disease. Protein phosphatase 2A (PP2A) encompasses a large subfamily of enzymes that remove phosphate groups from serine/threonine residues within phosphoproteins. The heterogeneity in PP2A structure, which arises from the grouping of different catalytic, scaffolding and regulatory subunit isoforms, creates distinct populations of catalytically active enzymes (i.e. holoenzymes) that localise to different parts of the cell. This structural complexity, combined with other regulatory mechanisms, such as interaction of PP2A heterotrimers with accessory proteins and post-translational modification of the catalytic and/or regulatory subunits, enables PP2A holoenzymes to target phosphoprotein substrates in a highly specific manner. In this review, we summarise the roles of PP2A in cardiac physiology and disease. PP2A modulates numerous processes that are vital for heart function including calcium handling, contractility, beta-adrenergic signalling, metabolism and transcription. Dysregulation of PP2A has been observed in human cardiac disease settings, including heart failure and atrial fibrillation. Efforts are underway, particularly in the cancer field, to develop therapeutics targeting PP2A activity. The development of small molecule activators of PP2A (SMAPs) and other compounds that selectively target specific PP2A holoenzymes (e.g. PP2A/B56 alpha and PP2A/B56 epsilon) will improve understanding of the function of different PP2A species in the heart, and may lead to the development of therapeutics for normalising aberrant protein phosphorylation in settings of cardiac remodelling and dysfunction.
查看更多>>摘要：It has been suggested that mitochondrial dysfunction underlies the myocardial injury seen following cardiorenal syndrome type 3 (CRS-3). Both mitophagy and the mitochondrial unfolded protein response (UPRmt) are protective programs that preserve mitochondrial homeostasis. Here, we explored whether Bax inhibitor-1 (BI-1) overexpression attenuates CRS-3-related myocardial injury through activation of mitophagy and the UPRmt in cardiomyocytes. Following CRS-3 induction via renal ischemia-reperfusion injury, BI-1 transgenic (BI1TG) mice showed greater preservation of myocardial integrity and relaxation function and less cardiomyocyte apoptosis than wild-type (WT) mice. Moreover, BI-1 overexpression attenuated CRS-3-mediated myocardial inflammation, as indicated by decreased MCP-1 and IL-6 expression and normalized ATP production in cardiomyocytes. After CRS-3 induction, mitophagy was inhibited in cardiomyocytes from WT mice, as indicated by both decreased Fundc1 transcription and mt-Keima fluorescence, and modest activation of the UPRmt, denoted by a slight increase in Atf6 mRNA levels. By contrast, activation of mitophagy and marked UPRmt upregulation were observed in cardiac tissue from BI1TG mice. shRNA-mediated silencing of Fundc1 or Atf6 greatly impaired mitochondrial metabolism and survival in cultured cardiomyocytes overexpressing BI-1. Thus, upregulation of BI-1 expression aimed at activating mitophagy and the UPRmt may represent a useful therapeutic approach for the treatment of CRS-3.
查看更多>>摘要：The pathogenesis of Legg-Calve & PRIME;-Perthes disease (LCPD) has not been fully elucidated, and studies on epigenetic changes that may contribute to the pathogenesis of LCPD are rare. MicroRNAs (miRNAs) are epigenetic modifications that play a critical role in gene regulation. This study aimed to determine the expression profiles of circulating exosomal miRNAs and examine the role of exosomal miRNAs in LCPD. Exosomes were extracted from the plasma of three patients with LCPD and three matched healthy volunteers. Total exosomal miRNAs were isolated, and next-generation sequencing and bioinformatic approaches were performed. The top 10 most differentially upregulated miRNAs were identified, and qRT-PCR validation was performed using additional 10 matches. In Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, plasma exosomes were used in verifying osteoclastogenesis and the endothelial dysfunction phenotypes involved. The elevated miRNAs in LCPD plasma exosomes were tested for osteoclastogenesis and endothelial dysfunction in vitro. Sequencing results revealed the expression profiles of plasma exosomal miRNAs with differential expression from the DESeqidentified miRNA profiles in LCPD versus controls in a pairwise comparison. Gene Ontology and KEGG pathway analyses indicated that the predicted target genes of different miRNAs were mainly enriched in the endothelial and osteoclast cells related to signaling pathways. Functional phenotype experiments showed that the plasma exosomes in the LCPD group promoted osteoclastogenesis and endothelial cell dysfunction. qRT-PCR experiments showed that nine miRNAs in circulating exosomes in LCPD patients were higher than those in the healthy controls. miR-3133, miR-4644, miR-4693-3p, and miR-4693-5p promoted endothelial dysfunction, and miR-3133, miR-4693-3p, miR-4693-5p, miR-141-3p and miR-30a promoted osteoclastogenesis in vitro. This study demonstrated that plasma exosomes from LCPD promote endothelial cell dysfunction and osteoclastogenesis likely through their miRNAs, which might contribute to the development of LCPD.
查看更多>>摘要：Dilated cardiomyopathies (DCM) represent a diverse group of cardiovascular diseases impacting the structure and function of the myocardium. To better treat these diseases, we need to understand the impact of such cardiomyopathies on critical signalling pathways that drive disease progression downstream of receptors we often target therapeutically. Our understanding of cellular signalling events has progressed substantially in the last few years, in large part due to the design, validation and use of biosensor-based approaches to studying such events in cells, tissues and in some cases, living animals. Another transformative development has been the use of human induced pluripotent stem cells (hiPSCs) to generate disease-relevant models from individual patients. We highlight the importance of going beyond monocellular cultures to incorporate the influence of paracrine signalling mediators. Finally, we discuss the recent coalition of these approaches in the context of DCM. We discuss recent work in generating patient-derived models of cardiomyopathies and the utility of using signalling biosensors to track disease progression and test potential therapeutic strategies that can be later used to inform treatment options in patients.
查看更多>>摘要：Background: The apoptosis and inflammation in cardiac microvascular endothelial cells (CMECs) promote the development of coronary microvascular dysfunction (CMD). The present study aimed to explore the role of E3 ubiquitin ligase mind bomb 1 (MIB1) in the apoptosis and inflammation in CMECs during CMD.Methods: In vivo, CMD in rats was induced by sodium laurate injection. In vitro, rat primary CMECs were stim-ulated by homocysteine (Hcy). The apoptosis of CMECs was measured using flow cytometry. The inflammation of CMECs was evaluated by the level of tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta). The interplay between MIB1 and mitogen-activated protein kinase kinase kinase 5 (map3k5, also called ASK1) was measured using Co-immunoprecipitation.Results: MIB1 expression was decreased and ASK1 expression was increased in the heart tissues of CMD rats and Hcy-treated CMECs. MIB1 overexpression decreased fibrinogen-like protein 2 (FGL2) secretion, inflammation, and apoptosis induced by Hcy in CMECs. Meanwhile, MIB1 overexpression decreased the protein levels of ASK1 and p38, while not affected ASK1 mRNA levels. The following mechanism experiments revealed that MIB1 downregulated ASK1 expression by increasing its ubiquitination. ASK1 overexpression reversed the inhibitory effect of MIB1 on FGL2 secretion, apoptosis, inflammation, and p38 activation in Hcy-treated CMECs. In CMD rats, MIB1 overexpression partly retarded CMD progression, manifesting as increased coronary capillary density and decreased microthrombi formation.Conclusion: MIB1 overexpression relieved apoptosis and inflammation of CMECs during CMD by targeting the ASK1/p38 pathway.
NSTL
Elsevier