Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens

Lange, Martin; Fujikawa, Tatsuya; Koulova, Anna; Kang, Sona; Griffin, Michael; Lassaletta, Antonio D.; Erat, Anna; Tobiasch, Edda; Bianchi, Cesario; Elmadhun, Nassrene Y.; Sellke, Frank W.; Usheva, Anny

doi:10.4161/cc.27056

Cited by 11 publications

(7 citation statements)

References 28 publications

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“…Our target prediction and network analyses also imply involvement of the investigated miRNAs in atherosclerosis-related processes, since targets as FOXO1 and CDK2 were previously shown to have key roles in the development of atherosclerosis, including angiogenesis, oxidative stress and proliferation of smooth muscle cells [33, 34]. Interestingly, both FOXO1 and MAPK14—another important node in our network—were also implicated in the development of heart failure [35, 36], therefore the identified targets may reflect key regulating mechanisms in both atherosclerotic disease and heart failure.…”

Section: Discussionmentioning

confidence: 94%

Low circulating microRNA levels in heart failure patients are associated with atherosclerotic disease and cardiovascular-related rehospitalizations

et al. 2017

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ObjectiveCirculating microRNAs (miRNAs) have been implicated in both heart failure and atherosclerotic disease. The aim of this study was to examine associations between heart failure specific circulating miRNAs, atherosclerotic disease and cardiovascular-related outcome in patients with heart failure.MethodsThe levels of 11 heart failure-specific circulating miRNAs were compared in plasma of 114 heart failure patients with and without different manifestations of atherosclerotic disease. We then studied these miRNAs in relation to biomarkers associated to atherosclerosis and to cardiovascular-related rehospitalizations during 18 months of follow-up.ResultsAt least one manifestation of atherosclerotic disease was found in 70 (61%) of the heart failure patients. A consistent trend was found between an increasing number of manifestations of atherosclerosis (peripheral arterial disease in specific), and lower levels of miR-18a-5p, miR-27a-3p, miR-199a-3p, miR-223-3p and miR-652-3p (all P < 0.05). Target prediction and network analyses identified several interactions between miRNA targets and biomarkers related to inflammation, angiogenesis and endothelial dysfunction. Lower miRNA levels were associated with higher levels of these atherosclerosis-related biomarkers. In addition, lower miRNA levels were significantly associated with rehospitalizations due to cardiovascular causes within 18 months, with let-7i-5p as strongest predictor [HR 2.06 (95% CI 1.29–3.28), C-index 0.70, P = 0.002].ConclusionsA consistent pattern of lower levels of circulating miRNAs was found in heart failure patients with atherosclerotic disease, in particular peripheral arterial disease. In addition, lower levels of miRNAs were associated with higher levels of biomarkers involved in atherosclerosis and an increased risk of a cardiovascular-related rehospitalization.Electronic supplementary materialThe online version of this article (doi:10.1007/s00392-017-1096-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 94%

Low circulating microRNA levels in heart failure patients are associated with atherosclerotic disease and cardiovascular-related rehospitalizations

et al. 2017

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“…Frozen sections (12 μm in thickness) or formalin fixed tissue sections of myocardium from the non-ischemic territories were stained with anti- MGEA5 (OGA) antibody [EPR7154 (B)], (Abcam); anti-OGT (ARP49154_P050- FITC, AVIVA); Anti-O-Linked N-Acetylglucosamine Antibody, clone RL2 (SigmaAldrich); α- Smooth Muscle actin—FITC antibody (Vector); anti- YY1 antibody—ChIP Grade (ab38422) (ABcam); Anti-SP1 antibody—ChIP Grade (ab13370) (ABcam). WGA affinity chromatography was conducted as in [12, 25]. The equal loading and transfer are monitored by staining the membranes after transfer with Ponceau S. The protein concentration is measured with the BCA Assay kit (Pierce).…”

Section: Methodsmentioning

confidence: 99%

Robust effect of metabolic syndrome on major metabolic pathways in the myocardium

et al. 2019

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Although the high-fat-diet-induced metabolic syndrome (MetS) is a precursor of human cardiac pathology, the myocardial metabolic state in MetS is far from clear. The discrepancies in metabolite handling between human and small animal models and the difficulties inherent in obtaining human tissue complicate the identification of the myocardium-specific metabolic response in patients. Here we use the large animal model of swine that develops the hallmark criteria of human MetS. Our comparative metabolomics together with transcriptomics and computational nonnegative matrix factorization (NMF) interpretation of the data exposes significant decline in metabolites related to the fatty acid oxidation, glycolysis, and pentose phosphate pathway. Behind the reversal lies decreased expression of enzymes that operate in the pathways. We showed that diminished glycogen deposition is a metabolic signature of MetS in the pig myocardium. The depletion of glycogen arises from disbalance in expression of genes that break down and synthesize glycogen. We show robust acetoacetate accumulation and activated expression of key enzymes in ketone body formation, catabolism and transporters, suggesting a shift in fuel utilization in MetS. A contrasting enrichment in O-GlcNAcylated proteins uncovers hexosamine pathway and O-GlcNAcase (OGA) expression involvement in the myocardial response to MetS. Although the hexosamine biosynthetic pathway (HBP) activity and the availability of the UDP-GlcNAc substrate in the MetS myocardium is low, the level of O-GlcNacylated proteins is high as the O-GlcNacase is significantly diminished. Our data support the perception of transcriptionally driven myocardial alterations in expression of standard fatty acids, glucose metabolism, glycogen, and ketone body related enzymes and subsequent paucity of their metabolite products in MetS. This aberrant energy metabolism in the MetS myocardium provide insight into the pathogenesis of CVD in MetS.

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“…PRKACA (cAMP dependent kinase) can maintain circulating platelets in a resting state by phosphorylating proteins in numerous platelet-inhibitory pathways [ 74 ]. CDK2 (Cyclin-dependent kinase 2) plays an important role in altering the phosphorylation profile of retinoblastoma tumor suppressor protein (Rb) in coronary artery smooth muscle cells (SMCs) as well as the proliferative response of these cells to mitogenic stimulation [ 75 ]. Moreover, MAO-B (amine oxidase B) inhibitors have been shown to be potentially beneficial for treating cardiovascular pathologies [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Natural formulas and the nature of formulas: Exploring potential therapeutic targets based on traditional Chinese herbal formulas

Zhang

et al. 2017

PLoS ONE

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By comparing the target proteins (TPs) of classic traditional Chinese medicine (TCM) herbal formulas and modern drugs used for treating coronary artery disease (CAD), this study aimed to identify potential therapeutic TPs for treating CAD. Based on the theory of TCM, the Xuefu-Zhuyu decoction (XZD) and Gualou-Xiebai-Banxia decoction (GXBD), both of which are classic herbal formulas, were selected for treating CAD. Data on the chemical ingredients and corresponding TPs of the herbs in these two formulas and data on modern drugs approved for treating CAD and related TPs were retrieved from professional TCM and bioinformatics databases. Based on the associations between the drugs or ingredients and their TPs, the TP networks of XZD, GXBD, and modern drugs approved for treating CAD were constructed separately and then integrated to create a complex master network in which the vertices represent the TPs and the edges, the ingredients or drugs that are linked to the TPs. The reliability of this master network was validated through statistical tests. The common TPs of the two herbal formulas have a higher possibility of being targeted by modern drugs in comparison with the formula-specific TPs. A total of 114 common XZD and GXBD TPs that are not yet the target of modern drugs used for treating CAD should be experimentally investigated as potential therapeutic targets for treating CAD. Among these TPs, the top 10 are NOS3, PTPN1, GABRA1, PRKACA, CDK2, MAOB, ESR1, ADH1C, ADH1B, and AKR1B1. The results of this study provide a valuable reference for further experimental investigations of therapeutic targets for CAD. The established method shows promise for searching for potential therapeutic TPs based on herbal formulas. It is crucial for this work to select beneficial therapeutic targets of TCM, typical TCM syndromes, and corresponding classic formulas.

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Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens

Abstract: (2014) Arterial territory-specific phosphorylated retinoblastoma protein species and CDK2 promote differences in the vascular smooth muscle cell response to mitogens, Cell Cycle, 13:2, 315-323,

Cited by 11 publications

References 28 publications

Low circulating microRNA levels in heart failure patients are associated with atherosclerotic disease and cardiovascular-related rehospitalizations

Low circulating microRNA levels in heart failure patients are associated with atherosclerotic disease and cardiovascular-related rehospitalizations

Robust effect of metabolic syndrome on major metabolic pathways in the myocardium

Natural formulas and the nature of formulas: Exploring potential therapeutic targets based on traditional Chinese herbal formulas

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