Proteolytic degradation of hemoglobin by endogenous lysosomal proteases gives rise to bioactive peptides: hemorphins

Fruitier, Ingrid; Garreau, Isabelle; Lacroix, André; Cupo, A.; Piot, Jean–Marie

doi:10.1016/s0014-5793(99)00271-9

Cited by 39 publications

(25 citation statements)

References 36 publications

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“…These so-called "hemorphins" are ligands for opioid and possibly G-protein-coupled receptors and have roles in processes as diverse as blood pressure regulation, neurotransmission, and neutrophil activity (43)(44)(45)(46)(47)(48). The best characterized hemorphin, LVVH-7 (derived from ␤-globin), is an inhibitor of angiotensin-converting enzyme (a protein found at the highest concentration in the mammalian lung), and can help regulate blood pressure through the renin-angiotensin system (45).…”

Section: Discussionmentioning

confidence: 99%

“…The best characterized hemorphin, LVVH-7 (derived from ␤-globin), is an inhibitor of angiotensin-converting enzyme (a protein found at the highest concentration in the mammalian lung), and can help regulate blood pressure through the renin-angiotensin system (45). Interestingly, although hemorphins were previously thought to be produced solely by erythrocyte-scavenging macrophages (44), the cathepsin proteases involved in their synthesis are also expressed by ATII cells, where they are involved in post-translational processing of surfactant proteins (43,49,50). In addition, LVVH-7 has been found in the brochoalveolar lavage fluid of patients with certain types of lung cancer (51).…”

Section: Discussionmentioning

confidence: 99%

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Hemoglobin Is Expressed by Alveolar Epithelial Cells

Newton

Rao

Dluhy

et al. 2006

Journal of Biological Chemistry

146

124

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Hemoglobin gene expression in non-erythroid cells has been previously reported in activated macrophages from adult mice and lens cells, and recent studies indicate that alveolar epithelial cells can be derived from hematopoietic stem cells. Our laboratory has now produced strong evidence that hemoglobin is expressed by alveolar type II (ATII) cells and Clara cells, the primary producers of pulmonary surfactant. ATII cells are also closely involved in innate immunity within the lung and are stem cells that differentiate into alveolar type I cells. Reverse transcriptase-PCR was used to measure the expression of transcripts from the ␣-and ␤-globin gene clusters in several human and rodent pulmonary epithelial cells. Surprisingly, the two major globin mRNAs characteristic of adult erythroid precursor cells were clearly expressed in human A549 and H441 cell lines, mouse MLE-15 cells, and primary ATII cells isolated from normal rat and mouse lungs. DNA sequencing verified that these PCR products were indeed the result of specific amplification of globin gene cDNAs. These alveolar epithelial cells also expressed the corresponding hemoglobin protein subunits as determined by Western blotting, and tandem mass spectrometry sequencing was used to verify the presence of both ␣-and ␤-globin polypeptides in rat primary ATII cells. The function of hemoglobin expression by cells of the pulmonary epithelium will be determined by future studies, but this novel finding could potentially have important implications for the physiology and pathology of the lung.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hemoglobin Is Expressed by Alveolar Epithelial Cells

Newton

Rao

Dluhy

et al. 2006

Journal of Biological Chemistry

146

124

View full text Add to dashboard Cite

show abstract

“…Small cathepsin-mediated proteolytic cleavage products of hemoglobin proteins (hemorphins) have cytotoxic and anti-proliferative effects on cells and act as "atypical" opioid peptides (Fruitier et al, 1999, Blishchenko et al, 2002, Ianzer et al, 2006. Finally, truncated hemoglobins (trHbs) are small hemoproteins (20-40 residues shorter than full-length mammalian hemoglobin chains found in bacteria, higher plants, and unicellular eukaryotes) that define a distinct phylogenetic group within the globin super-family (Nardini et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Developmentally regulated expression of hemoglobin subunits in avascular tissues

Mansergh¹,

Hunter²,

Geatrell³

et al. 2008

Int. J. Dev. Biol.

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We investigated the spatio-temporal profile of hemoglobin subunit expression in developing avascular tissues. Significant up-regulation of hemoglobin subunits was identified in microarray experiments comparing blastocyst inner cell masses with undifferentiated embryonic stem (ES) cells. Hemoglobin expression changes were confirmed using embryoid bodies (derived from in vitro differentiation of ES cells) to model very early development at pre-vascular stages of embryogenesis; i.e. prior to hematopoiesis. We also demonstrate, using RT-PCR, Western blotting and immunocytochemistry, expression of adult and fetal mouse hemoglobin subunits in the avascular ocular lens at various stages of development and maturation. Hemoglobin proteins were expressed in lens epithelial cells (cytoplasmic) and cortical lens fiber cells (nuclear and cellsurface-associated); however, a sensitive heme assay demonstrated negligible levels of heme in the developing lens postnatally. Hemoglobin expression was also observed in the developing eye in corneal endothelium and retinal ganglion cells. Gut sections showed, in addition to erythrocytes, hemoglobin protein staining in rare, individual villus epithelial cells. These results suggest a paradigm shift: hemoglobin subunits are expressed in the avascular lens and cornea and in prehematopoietic embryos. It is likely, therefore, that hemoglobin subunits have novel developmental roles; the absence of the heme group from the lens would indicate that at least some of these functions may be independent of oxygen metabolism. The pattern of expression of hemoglobin subunits in the perinuclear region during lens fiber cell differentiation, when denucleation is taking place, may indicate involvement in the apoptosis-like signaling processes occurring in differentiating lens fiber cells.

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“…In this study, we focused on moderate- to high-abundance plasma proteins and their fragments, resulting in novel findings regarding their phase-specific relevance and capacity to be used as biomarkers of liver regeneration after PHx. A growing body of evidence suggests that altered protease activities are involved in many diseases and could potentially generate a large number of peptides and small proteins [35]. They are thought to be released from their parent proteins by endoproteolytic cleavage, followed by the variable trimming of released peptides by aminopeptidases and carboxypeptidases [36].…”

Section: Discussionmentioning

confidence: 99%

Chronological Profiling of Plasma Native Peptides after Hepatectomy in Pigs: Toward the Discovery of Human Biomarkers for Liver Regeneration

Iguchi

Hatano

Nirasawa³

et al. 2017

PLoS ONE

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Liver regeneration after partial hepatectomy (PHx) is a time-dependent process, which is tightly regulated by multiple signaling cascades. Failure of this complex process leads to posthepatectomy liver failure (PHLF), which is associated with a high rate of mortality. Thus, it is extremely important to establish a useful biomarker of liver regeneration to help prevent PHLF. Here, we hypothesized that alterations in the plasma peptide profile may predict liver regeneration following PHx and hence we set up a diagnostic platform for monitoring posthepatectomy outcome. We chronologically analyzed plasma peptidomic profiles of 5 partially hepatectomized microminipigs using the ClinProtTM system, which consists of magnetic beads and MALDI-TOF/TOF MS. We identified endogenous circulating peptides specific to each phase of the postoperative course after PHx in pigs. Notably, peptide fragments of histones were detected immediately after PHx; the presence of these fragments may trigger liver regeneration in the very acute phase after PHx. An N-terminal fragment of hemoglobin subunit α (3627 m/z) was detected as an acute-phase-specific peptide. In the recovery phase, the short N-terminal fragments of albumin (3028, 3042 m/z) were decreased, whereas the long N-terminal fragment of the protein (8926 m/z) was increased. To further validate and extract phase-specific biomarkers using plasma peptidome after PHx, plasma specimens of 4 patients who underwent PHx were analyzed using the same method as we applied to pigs. It revealed that there was also phase-specificity in peptide profiles, one of which was represented by a fragment of complement C4b (2378 m/z). The strategy described herein is highly efficient for the identification and characterization of peptide biomarkers of liver regeneration in a swine PHx model. This strategy is feasible for application to human biomarker studies and will yield clues for understanding liver regeneration in human clinical trials.

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Proteolytic degradation of hemoglobin by endogenous lysosomal proteases gives rise to bioactive peptides: hemorphins

Cited by 39 publications

References 36 publications

Hemoglobin Is Expressed by Alveolar Epithelial Cells

Hemoglobin Is Expressed by Alveolar Epithelial Cells

Developmentally regulated expression of hemoglobin subunits in avascular tissues

Chronological Profiling of Plasma Native Peptides after Hepatectomy in Pigs: Toward the Discovery of Human Biomarkers for Liver Regeneration

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