Dynamics of angiogenesis in ischemic areas of the infarcted heart

Kobayashi, Koichi S.; Maeda, Kengo; Takefuji, Mikito; Kikuchi, Ryosuke; Morishita, Yoshihiro; Hirashima, Masanori; Murohara, Toyoaki

doi:10.1038/s41598-017-07524-x

Cited by 75 publications

(70 citation statements)

References 35 publications

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“…Although much of the infarct area becomes apoptotic or necrotic within a few days after MI, the border zone has been shown to be a highly hypoxic region with active HIF1 signaling (19,22). Our data support these findings, as seen by the upregulation of both HIF1 and Pkm2 in the infarct and border regions after injury.…”

Section: Discussionsupporting

confidence: 85%

HIF1 mediates a switch in pyruvate kinase isoforms after myocardial infarction

Williams

Khadka

Tang

et al. 2018

Physiological Genomics

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Alternative splicing of RNA is an underexplored area of transcriptional response. We expect that early changes in alternatively spliced genes may be important for responses to cardiac injury. Hypoxia inducible factor 1 (HIF1) is a key transcription factor that rapidly responds to loss of oxygen through alteration of metabolism and angiogenesis. The goal of this study was to investigate the transcriptional response after myocardial infarction (MI) and to identify novel, hypoxia-driven changes, including alternative splicing. After ligation of the left anterior descending artery in mice, we observed an abrupt loss of cardiac contractility and upregulation of hypoxic signaling. We then performed RNA sequencing on ischemic heart tissue 1 and 3 days after infarct to assess early transcriptional changes and identified 89 transcripts with altered splicing. Of particular interest was the switch in Pkm isoform expression (pyruvate kinase, muscle). The usually predominant Pkm1 isoform was less abundant in ischemic hearts, while Pkm2 and associated splicing factors (hnRNPA1, hnRNPA2B1, Ptbp1) rapidly increased. Despite increased Pkm2 expression, total pyruvate kinase activity remained reduced in ischemic myocardial tissue. We also demonstrated HIF1 binding to PKM by chromatin immunoprecipitation, indicating a direct role for HIF1 in mediating this isoform switch. Our study provides a new, detailed characterization of the early transcriptome after MI. From this analysis, we identified an HIF1-mediated alternative splicing event in the PKM gene. Pkm1 and Pkm2 play distinct roles in glycolytic metabolism and the upregulation of Pkm2 is likely to have important consequences for ATP synthesis in infarcted cardiac muscle.

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Section: Discussionsupporting

confidence: 85%

HIF1 mediates a switch in pyruvate kinase isoforms after myocardial infarction

Williams

Khadka

Tang

et al. 2018

Physiological Genomics

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“…This heterogeneity could contribute to the variability of outcomes seen post-myocardial infarction in our patient population (81,82). Additionally, areas of myocardial damage after infarction are known to undergo angiogenesis in response to chronic hypoxic stress associated with subsequent fibrosis formation (82,83). Therefore, the formation of the coronary vasculature and its associated microvasculature could be of significant clinical importance.…”

Section: New Insight In Coronary Vasculature Development With Scrna-seqmentioning

confidence: 98%

“…This heterogeneity contributes to a mosaicism of oxygen delivery to various parts of the myocardium and larger arteries (80). This heterogeneity could contribute to the variability of outcomes seen post-myocardial infarction in our patient population (81,82). Additionally, areas of myocardial damage after infarction are known to undergo angiogenesis in response to chronic hypoxic stress associated with subsequent fibrosis formation (82,83).…”

Section: New Insight In Coronary Vasculature Development With Scrna-seqmentioning

confidence: 99%

Single-Cell RNA Sequencing of the Cardiovascular System: New Looks for Old Diseases

Chaudhry

Isherwood

Bawa

et al. 2019

Front. Cardiovasc. Med.

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Cardiovascular disease encompasses a wide range of conditions, resulting in the highest number of deaths worldwide. The underlying pathologies surrounding cardiovascular disease include a vast and complicated network of both cellular and molecular mechanisms. Unique phenotypic alterations in specific cell types, visualized as varying RNA expression-levels (both coding and non-coding), have been identified as crucial factors in the pathology underlying conditions such as heart failure and atherosclerosis. Recent advances in single-cell RNA sequencing (scRNA-seq) have elucidated a new realm of cell subpopulations and transcriptional variations that are associated with normal and pathological physiology in a wide variety of diseases. This breakthrough in the phenotypical understanding of our cells has brought novel insight into cardiovascular basic science. scRNA-seq allows for separation of widely distinct cell subpopulations which were, until recently, simply averaged together with bulk-tissue RNA-seq. scRNA-seq has been used to identify novel cell types in the heart and vasculature that could be implicated in a variety of disease pathologies. Furthermore, scRNA-seq has been able to identify significant heterogeneity of phenotypes within individual cell subtype populations. The ability to characterize single cells based on transcriptional phenotypes allows researchers the ability to map development of cells and identify changes in specific subpopulations due to diseases at a very high throughput. This review looks at recent scRNA-seq studies of various aspects of the cardiovascular system and discusses their potential value to our understanding of the cardiovascular system and pathology.

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“…Ultrastructurally, 7 days after the production of EMI, the border zone of the lesion is characterized by the presence of frequent myofibroblasts, and consequently by matrix remodeling (Manole et al, 2011). However, the EMI model in mice showed that the border zone of the lesion is featured by angiogenesis based on endocardium and under VEGF 2 signaling (Kobayashi et al, 2017). In the rat EMI model, previous published data showed that the border zone of a 4-week-old EMI lesion is still presenting significant neo-angiogenesis, in which numerically increased telocytes (which have VEGF and NOS 2 positive expression) are active players (Manole et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Areas of Cartilaginous and Osseous Metaplasia After Experimental Myocardial Infarction in Rats

Manole

Marinescu

Marta³

et al. 2018

The Anatomical Record

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The presence of hyaline cartilage has been previously documented in heart tissue of different vertebrates, ranging from birds to superior mammals. However, there is scarce published data regarding the appearance of focal deposits of hyaline‐like cartilage within the hearts of laboratory rats. Few mechanisms that could trigger the appearance of this type of cartilage in heart were hypothesized (e.g., mechanical stress, ageing). Using different microscopy techniques this report confirms the presence of hyaline cartilage and bone in Wistar rats, which underwent left anterior coronary artery ligation for experimental myocardial infarction. The presented (ultra)structural evidence of focal chondroid metaplasia in the papillary muscles and close to the insertion point in the ventricular mass of the infarcted heart suggests a structural adaptation of cardiac myocardium to the newly acquired kinetics of left ventricular wall, after experimental myocardial infarction. Specific cartilaginous matrix proteins are known to mediate cardiac extracellular matrix remodeling, and this study provides evidence of a complete transition to a cartilaginous pattern in postinfarcted heart, which may nonetheless constitute a supplemental risk factor of a further heart failure condition. Moreover, for heart focal chondrogenesis, we also presume the involvement of the cellular and molecular inflammatory milieu that dominates the first 24 hr border zone landscape of the experimental myocardial infarction lesion. Anat Rec, 302:947–953, 2019. © 2018 Wiley Periodicals, Inc.

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Dynamics of angiogenesis in ischemic areas of the infarcted heart

Cited by 75 publications

References 35 publications

HIF1 mediates a switch in pyruvate kinase isoforms after myocardial infarction

HIF1 mediates a switch in pyruvate kinase isoforms after myocardial infarction

Single-Cell RNA Sequencing of the Cardiovascular System: New Looks for Old Diseases

Areas of Cartilaginous and Osseous Metaplasia After Experimental Myocardial Infarction in Rats

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