Thymosin β4 and Ac-SDKP: Tools to mend a broken heart

Rossdeutsch, Alex; Smart, Nicola; Riley, Paul R.

doi:10.1007/s00109-007-0243-9

Cited by 24 publications

(25 citation statements)

References 47 publications

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“…The Ac-SDKP peptide has been implicated in a number of biological processes, including fibrosis, proliferation, and angiogenesis (53–55). While thymosin β4 is expressed in the brain, the Ac-SDKP peptide has mostly been studied in the periphery, specifically the cardiovascular system.…”

Section: Discussionmentioning

confidence: 99%

Peptidomics of Prolyl Endopeptidase in the Central Nervous System

et al. 2009

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Prolyl endopeptidase (Prep) is a member of the prolyl peptidase family and is of interest due to its unique biochemistry and connections to cognitive function. Using an unbiased mass spectrometry (MS)-based peptidomics platform, we identified Prep regulated peptides in the central nervous system (CNS) of mice by measuring changes in the peptidome as a function of Prep activity. This approach was validated by the identification of known Prep substrates, such as the neuropeptide substance P and thymosin-β4, the precursor to the bioactive peptide Ac-SDKP. In addition to these known substrates, we also discovered that Prep regulates many additional peptides, including additional bioactive peptides and proline rich peptides (PRPs). Biochemical experiments confirmed that some of these Prep regulated peptides are indeed substrates of the enzyme. Moreover, these experiments also supported the known preference of Prep for shorter peptides, while revealing a previously unknown cleavage site specificity of Prep when processing certain multi-proline containing peptides, including PRPs. The discovery of Prep regulated peptides implicates Prep in new biological pathways and provides insights into the biochemistry of this enzyme.Prolyl endopeptidase (Prep), also commonly referred to as prolyl oligopeptidase (POP) (EC 3.4.21.26), was first identified as an oxytocin cleaving activity in the human uterus (1) and is part of the prolyl peptidase family of enzymes (2,3). Other mammalian members of the prolyl peptidase family include the dipeptidyl peptidases, such as the anti-diabetic target dipeptidyl peptidase 4 (DPP4) (4), and the recently characterized prolyl endopeptidase-like (PrepL) (5), which has been genetically linked to hypotoniacystinuria syndrome (HCS) (6)(7)(8). Prep has been of general interest because of its unique biochemical activity as a proline endopeptidase. Unlike the dipeptidyl peptidases, which are restricted to N-terminal dipeptide cleavage (3,9), Prep proteolysis occurs at internal prolines in a peptide (10)(11)(12). On the basis of the known preference of Prep for cleavage at a proline, many proline-containing bioactive peptides have been tested, and identified, as Prep substrates in vitro (12). These substrates range from the tripeptide, thyrotropin-releasing hormone, to a 31 amino acid peptide, beta endorphin (2,13).Correspondence to: Alan Saghatelian, saghatelian@chemistry.harvard.edu. *To whom correspondence should be addressed. Phone: (617) . saghatelian@chemistry.harvard.edu. Supporting Information. ABPP gels with prolyl peptidases and S17092, Prep activity assay showing heat inactivation, graph with fold changes of peptides at one hour and 4 hours of inhibition, graph of CGRP(1-37) levels after one hour of inhibition, kinetic plots of CGRP analogs with wild type and mutant Prep, table with kinetic parameters of CGRP analogs with wild type and mutant Prep with kcat/Km calculated as second order rate constant, MALDI-MS spectrum of the reaction of unacetylated Hsp12a(2-23) with Prep, circula...

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Section: Discussionmentioning

confidence: 99%

Peptidomics of Prolyl Endopeptidase in the Central Nervous System

et al. 2009

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“…47 ACE is the major peptidase that acts to degrade Ac-SDKP; 48 after acute ACE inhibition, plasma levels of Ac-SDKP increase by approximately five-fold in of AT1 receptor signaling appear deviant in their developmental patterns of cytokine expression. These studies have to be viewed with caution since the studies used GM-CSF induced dendritic cells, which may not represent the diversified populations of dendritic cells in vivo.…”

Section: Ac-sdkpmentioning

confidence: 99%

The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis

Shen

Bernstein

2011

Cell Cycle

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T he concept of a local bone marrow renin-angiotensin system (RAS) has been introduced and accumulating evidence suggests that the local RAS is actively involved in hematopoiesis. Angiotensin converting enzyme (ACE) is a key player in the RAS and makes the final effector angiotensin II. Besides angiotensin II, ACE also regulates a panel of bioactive peptides, such as substance P, Ac-SDKP and angiotensin 1-7. These peptides have also been individually reported in the regulation of pathways of hematopoiesis. In this setting, an ACE-regulated peptide network orchestrating hematopoiesis has emerged. Here, we focus on this peptide network and discuss the roles of ACE and its peptides in aspects of hematopoiesis. Special attention is given to the recent revelation that ACE is a bona fide marker of hematopoietic stem cells.

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“…Ac-SDKP is derived from the 43 amino acid peptide thymosin β4 (Tβ4) which has cardioprotective properties in acute myocardial infarction [47]. It was proposed that some of the therapeutically beneficial effects of Tβ4 may be due to action of Ac-SDKP [47].…”

Section: Hypothesis Of An Imbalance Between the Inhibition And Activamentioning

confidence: 99%

“…It was proposed that some of the therapeutically beneficial effects of Tβ4 may be due to action of Ac-SDKP [47]. Since intrapericardially administered fibroblast growth factor of mol.…”

Section: Hypothesis Of An Imbalance Between the Inhibition And Activamentioning

confidence: 99%

Intrapericardial procedures for cardiac regeneration by stem cells

Rupp

Alter³

et al. 2010

Herz

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In view of the only modest functional and anatomical improvements achieved by bone marrow-derived cell transplantation in patients with heart disease, the question was addressed whether the intracoronary, transcoronary-venous, and intramyocardial delivery routes are adequate. It is hypothesized that an intrapericardial delivery of stem cells or activators of resident cardiac stem cells increases therapeutic benefits. From such an intrapericardial depot, cells or modulating factors, such as thymosin β4 or Ac-SDKP, are expected to reach the myocardium with sustained kinetics. Novel tools which provide access to the pericardial space even in the absence of pericardial effusion are, therefore, described. When the pericardium becomes attached to the suction head (monitored by an increase in negative pressure), the pericardium is lifted from the epicardium ("AttachLifter"). The opening of the suction head ("Attacher") is narrowed by flexible clamps which grab the tissue and improve the vacuum seal in the case of uneven tissue. A ridge, i.e.,"needle guidance", on the suction head excludes injury to the epicardium, whereby the pericardium is punctured by a needle which resides outside the suction head. A fiberscope can be used to inspect the pericardium prior to puncture. Based on these procedures, the role of the pericardial space and the presence of pericardial effusion in cardiac regeneration can be assessed.

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Thymosin β4 and Ac-SDKP: Tools to mend a broken heart

Cited by 24 publications

References 47 publications

Peptidomics of Prolyl Endopeptidase in the Central Nervous System

Peptidomics of Prolyl Endopeptidase in the Central Nervous System

The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis

Intrapericardial procedures for cardiac regeneration by stem cells

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