Prolylcarboxypeptidase promotes angiogenesis and vascular repair

Adams, Gregory N.; Stavrou, Evi X.; Fang, Chao; Merkulova, Alona; Alaiti, Mohamad Amer; Nakajima, Kohsuke; Morooka, Toshifumi; Merkulov, Sergei; LaRusch, Gretchen A.; Simon, Daniel I.; Jain, Mukesh K.; Schmaier, Alvin H.

doi:10.1182/blood-2012-10-460360

Cited by 51 publications

(49 citation statements)

References 49 publications

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“…In the juvenile clusters, hub genes whose biological functions are implicated in angiogenesis dominated (Table 2): Esam [80] and Ets2 [81] in cluster J2, Prcp [82] and Fmnl3 [83] in cluster J3, Bcl6b [84], Robo4 [85], and Egr1 [86] in cluster J4. In addition to the angiogenesis-related genes, a gene involved in heart valve and septum development ( Adam19 [87] in cluster J1) was also identified as a juvenile cluster hub gene.…”

Section: Resultsmentioning

confidence: 99%

Transcriptome Dynamics and Potential Roles of Sox6 in the Postnatal Heart

Ichihashi

Peng

et al. 2016

PLoS ONE

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The postnatal heart undergoes highly coordinated developmental processes culminating in the complex physiologic properties of the adult heart. The molecular mechanisms of postnatal heart development remain largely unexplored despite their important clinical implications. To gain an integrated view of the dynamic changes in gene expression during postnatal heart development at the organ level, time-series transcriptome analyses of the postnatal hearts of neonatal through adult mice (P1, P7, P14, P30, and P60) were performed using a newly developed bioinformatics pipeline. We identified functional gene clusters by principal component analysis with self-organizing map clustering which revealed organized, discrete gene expression patterns corresponding to biological functions associated with the neonatal, juvenile and adult stages of postnatal heart development. Using weighted gene co-expression network analysis with bootstrap inference for each of these functional gene clusters, highly robust hub genes were identified which likely play key roles in regulating expression of co-expressed, functionally linked genes. Additionally, motivated by the role of the transcription factor Sox6 in the functional maturation of skeletal muscle, the role of Sox6 in the postnatal maturation of cardiac muscle was investigated. Differentially expressed transcriptome analyses between Sox6 knockout (KO) and control hearts uncovered significant upregulation of genes involved in cell proliferation at postnatal day 7 (P7) in the Sox6 KO heart. This result was validated by detecting mitotically active cells in the P7 Sox6 KO heart. The current report provides a framework for the complex molecular processes of postnatal heart development, thus enabling systematic dissection of the developmental regression observed in the stressed and failing adult heart.

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Section: Resultsmentioning

confidence: 99%

Transcriptome Dynamics and Potential Roles of Sox6 in the Postnatal Heart

Ichihashi

Peng

et al. 2016

PLoS ONE

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“…PRCP gt/gt mice have increased vessel ROS with reduced eNOS, uncoupled eNOS, reduced protein C activation due to reduced thrombomodulin expression, increased vascular tissue factor and plasminogen activator inhibitor (59). These animals also have reduced cell growth, angiogenesis, wound injury repair, ischemia/reperfusion repair, and increased arterial neointima/media growth after endothelial cell denudation (30). PRCP’s influence on vascular well-being has nothing to do with contact activation.…”

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confidence: 99%

Physiologic activities of the Contact Activation System

Schmaier

2014

Thrombosis Research

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The plasma contact activation (CAS) and kallikrein/kinin (KKS) systems consist of 4 proteins: factor XII, prekallikrein, high molecular weight kininogen, and the bradykinin B2 receptor. Murine genetic deletion of factor XII (F12−/−), prekallikrein (Klkb1−/−), high molecular weight kininogen (Kgn1−/−) and the bradykinin B2 receptor (Bdkrb2−/−) yield animals protected from thrombosis. With possible exception of F12−/− and Kgn1−/− mice, the mechanism(s) for thrombosis protection is not reduced contact activation. Bdkrb2−/− mice are best characterized and they are protected from thrombosis through over expression of components of the renin angiotensin system (RAS) leading to elevated prostacyclin with vascular and platelet inhibition. Alternatively, prolylcarboxypeptidase, a PK activator and degrader of angiotensin II, when deficient in the mouse leads to a prothrombotic state. Its mechanism for increased thrombosis also is mediated in part by components of the RAS. These observations suggest that thrombosis in mice of the CAS and KKS are mediated in part through the RAS and independent of reduced contact activation.

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“…Klkb1 −/− mice are also protected from ferric chloride-induced carotid artery thrombosis [35]. Likewise, prolonged PK inhibition by antisense oligonucleotides reduced thrombus formation, but acute pharmacological inhibition of PK results in an immediate prothrombotic state [31, 36, 37]. This information suggests that in chronic PK deficiency, there are some compensatory mechanisms that arise to give the animal a thrombosis protection phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…PRCP gt/gt mice are constitutively hypertensive, thrombotic, and lean [2, 31, 37]. They have reduced angiogenesis, ischemia/reper-fusion repair, and hyper-inflammation upon vascular injury [37]. PRCP gt/gt mice also have improved glucose tolerance and less insulin resistance [38].…”

Section: Discussionmentioning

confidence: 99%

Prolylcarboxypeptidase Independently Activates Plasma Prekallikrein (Fletcher Factor)

Wang¹,

Matafonov²,

Madkhali³

et al. 2014

CMM

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Prolylcarboxypeptidase isoform 1 (PRCP1) is capable of regulating numerous autocrines and hormones, such as angiotensin II, angiotensin III, αMSH1-13, and DesArg9 bradykinin. It does so by cleaving a C-terminal PRO-X bond. Recent work also indicates that the human PRCP1 activates plasma prekallikrein (PK) to kallikrein on endothelial cells through an uncharacterized mechanism. This study aims to identify PRCP1 binding interaction and cleavage site on PK. Recently, a cDNA encoding a novel splice variant of the human PRCP1 was identified. This isoform differed only in the N-terminal region of the deduced amino acid sequence. Using structural and functional studies, a combination of peptide mapping and site-directed mutagenesis approaches were employed to investigate the interaction of PRCP1 with PK. Three PRCP peptides, in decreasing order of potency, from 1) the N-terminus of the secreted protein, 2) spanning the opening of the active site pocket, and 3) in the dimerization region inhibit PRCP activation of PK on endothelial cells. Investigations also tested the hypothesis that PRCP cleavage site on PK is between its C-terminal Pro 637 (P637) and Ala 638 (A638). Recombinant forms of PK with C-terminal alanine mutagenesis or a stop codon is activated equally as wild type PK by PRCP. In conclusion, PRCP1 interacts with PK at multiple sites for PK activation. PRCP1 also enhances FXIIa activation of PK, suggesting that its activation site on PK is not identical to that of FXIIa.

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Prolylcarboxypeptidase promotes angiogenesis and vascular repair

Abstract: Key Points PRCP influences cell growth independent of its active site. PRCP loss has reduced angiogenesis, wound healing, and ischemic/wire injury repair.

Cited by 51 publications

References 49 publications

Transcriptome Dynamics and Potential Roles of Sox6 in the Postnatal Heart

Transcriptome Dynamics and Potential Roles of Sox6 in the Postnatal Heart

Physiologic activities of the Contact Activation System

Prolylcarboxypeptidase Independently Activates Plasma Prekallikrein (Fletcher Factor)

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