Cardiac proteomic responses to ischemia-reperfusion injury and ischemic preconditioning.
ABSTRACT Cardiac ischemia and ischemia-reperfusion (I/R) injury are major contributors to morbidity and mortality worldwide. Pathological mechanisms of I/R and the physiological mechanisms of ischemic preconditioning (IPC), which is an effective cardiac protective response, have been widely investigated in the last decade to search for means to prevent or treat this disease. Proteomics is a powerful analytical tool that has provided important information to identify target proteins and understand the underlying mechanisms of I/R and IPC. Here, we review the application of proteomics to I/R injury and IPC to discover target proteins. We analyze the functional meaning of the accumulated data on hundreds of proteins using various bioinformatics applications. In addition, we review exercise-induced proteomic alterations in the heart to understand the potential cardioprotective role of exercise against I/R injury. Further developments in the proteomic field that target specialized proteins will yield new insights for optimizing therapeutic targets and developing a wide range of therapeutic agents against ischemic heart disease.
SourceAvailable from: Manuel Portoles[Show abstract] [Hide abstract]
ABSTRACT: Changes in cardiomyocyte cytoskeletal components, a crucial scaffold of cellular structure, have been found in heart failure (HF); however, the altered cytoskeletal network remains to be elucidated. This study investigated a new map of cytoskeleton-linked alterations that further explain the cardiomyocyte morphology and contraction disruption in HF. RNA-Sequencing (RNA-Seq) analysis was performed in 29 human LV tissue samples from ischemic cardiomyopathy (ICM; n=13) and dilated cardiomyopathy (DCM, n=10) patients undergoing cardiac transplantation and six healthydonors (control, CNT) and up to 16 ICM, 13 DCM and 7 CNT tissue samples for qRT-PCR. Gene Ontology analysis of RNA-Seq data demonstrated that cytoskeletal processes are altered in HF. We identified 60 differentially expressed cytoskeleton-related genes in ICM and 58 genes in DCM comparing with CNT, hierarchical clustering determined that shared cytoskeletal genes have a similar behavior in both pathologies. We further investigated MYLK4, RHOU, and ANKRD1 cytoskeletal components. qRT-PCR analysis revealed that MYLK4 was downregulated (-2.2-fold; P<0.05) and ANKRD1 was upregulated (2.3-fold; P<0.01) in ICM patients vs CNT. RHOU mRNA levels showed a statistical trend to decrease (-2.9-fold). In DCM vs CNT, MYLK4 (-4.0-fold; P<0.05) and RHOU (-3.9-fold; P<0.05) were downregulated and ANKRD1 (2.5-fold; P<0.05) was upregulated. Accordingly, MYLK4 and ANKRD1 protein levels were decreased and increased, respectively, in both diseases. Furthermore, ANKRD1 and RHOU mRNA levels were related with LV function (P<0.05). In summary,we have found a new map of changes in the ICM and DCM cardiomyocyte cytoskeleton. ANKRD1 and RHOU mRNA levels were related with LV function wich emphasizes their relevance in HF. These new cytoskeletal changes may be responsible for altered contraction and cell architecture disruption in HF patients. Moreover, these results improve our knowledge on the role of cytoskeleton in functional and structural alterations in HF.Laboratory Investigation advance online publication, 7 April 2014; doi:10.1038/labinvest.2014.54.Laboratory Investigation 04/2014; DOI:10.1038/labinvest.2014.54 · 3.83 Impact Factor
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ABSTRACT: A middle cerebral artery occlusion-model was established in rats using the improved thread embolism method. Rats were treated with acupuncture at either Dazhui (DU14), Renzhong (DU26), Baihui (DU20), or a non-meridian point. Detection with protein-chip technology showed that the level of protein phosphorylation in both groups was upregulated or downregulated depending on the signaling pathway compared with the model group that did not receive acupuncture. Analysis of proteins showing downregulated phosphorylation revealed that five signaling pathways were activated in the acupuncture-treatment group, while only two were activated in the acupuncture- control group. In contrast, analysis of proteins showing upregulated phosphorylation revealed only one pathway was activated in the acupuncture-treatment group, whereas four pathways were activated in the acupuncture-control group. Furthermore, the number of activated proteins in the acupuncture-treatment group was not only higher than the acupuncture-control group, but unlike the acupuncture-control group, the majority of activated proteins were key proteins in the signaling pathways. Our findings indicate that acupuncture at specific points can activate multiple signaling pathways to promote the restoration of brain tissue following ischemic injury, and that this is based on a combination of effects resulting from multiple pathways, targets, and means.Neural Regeneration Research 08/2012; 7(24):1866-72. DOI:10.3969/j.issn.1673-5374.2012.24.004 · 0.23 Impact Factor
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ABSTRACT: The avalanche of integromics and panomics approaches shifted the deciphering of aging mechanisms from single molecular entities to communities of them. In this orientation, we explore the cardiac aging mechanisms - risk factor for multiple cardiovascular diseases - by capturing the micronome synergism and detecting longevity signatures in the form of communities (modules). For this, we developed a meta-analysis scheme that integrates transcriptome expression data from multiple cardiac-specific independent studies in mouse and human along with proteome and micronome interaction data in the form of multiple independent weighted networks. Modularization of each weighted network produced modules, which in turn were further analyzed so as to define consensus modules across datasets that change substantially during lifespan. Also, we established a metric that determines - from the modular perspective - the synergism of microRNA-microRNA interactions as defined by significantly functionally associated targets. The meta-analysis provided 40 consensus integromics modules across mouse datasets and revealed microRNA relations with substantial collective action during aging. Three modules were reproducible, based on homology, when mapped against human-derived modules. The respective homologs mainly represent NADH dehydrogenases, ATP synthases, cytochrome oxidases, Ras GTPases and ribosomal proteins. Among various observations, we corroborate to the involvement of miR-34a (included in consensus modules) as proposed recently; yet we report that has no synergistic effect. Moving forward, we determined its age-related neighborhood in which HCN3, a known heart pacemaker channel, was included. Also, miR-125a-5p/-351, miR-200c/-429, miR-106b/-17, miR-363/-92b, miR-181b/-181d, miR-19a/-19b, let-7d/-7f, miR-18a/-18b, miR-128/-27b and miR-106a/-291a-3p pairs exhibited significant synergy and their association to aging and/or cardiovascular diseases is supported in many cases by a disease database and previous studies. On the contrary, we suggest that miR-22 has not substantial impact on heart longevity as proposed recently. We revised several proteins and microRNAs recently implicated in cardiac aging and proposed for the first time modules as signatures. The integromics meta-analysis approach can serve as an efficient subvening signature tool for more-oriented better-designed experiments. It can also accelerate combinational multi-target microRNA therapy of age-related cardiovascular diseases across the continuum from prevention to detection, diagnosis, treatment and outcome.