Thrombospondin-1, Free Radicals, and the Coronary Microcirculation: The Aging Conundrum

LeBlanc, Amanda J.; Kelm, Natia Qipshidze

doi:10.1089/ars.2017.7292

Cited by 16 publications

(12 citation statements)

References 169 publications

(222 reference statements)

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“…Thrombospondin-1 (TSP1) is a matricellular protein that binds to cell surface receptors, modulating cellular function (59). Although a specific role for sperm function is not known, the TSP1 contributes to the production of reactive oxygen species (ROS) that -when in excess-can lead to cellular dysfunction (60). Moreover, SP concentration of TSP1 was recently correlated with boar ejaculates generating the smallest litter sizes in artificially inseminated sows (61).…”

Section: Resultsmentioning

confidence: 99%

The Proteome of Pig Spermatozoa Is Remodeled During Ejaculation

Pérez-Patiño

Parrilla

et al. 2019

Molecular & Cellular Proteomics

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The present study identified and quantified using iTRAQ-based LC-MS/MS, 1,723 and 1,602 proteins, respectively, in mature boar spermatozoa retrieved from cauda epididymis and three distinct fractions of the ejaculate. A total of 974 of the identified and 960 of the quantified proteins belonged to the Sus scrofa taxonomy. An ANOVA test revealed that 32 Sus scrofa proteins implicated in sperm function showed quantitative differences among sperm sources. The findings demonstrated that the proteome of boar spermatozoa is remodeled during ejaculation. Graphical Abstract Highlights• Proteome of mature boar spermatozoa from cauda epididymal and ejaculated sources were analyzed by iTRAQ-based LC-MS/MS.• 1,723 sperm proteins identified (974 of Sus scrofa taxonomy).• 1,602 sperm proteins quantified (960 of Sus scrofa taxonomy).• 32 Sus scrofa sperm proteins were differentially expressed among sperm sources.• The proteome of boar spermatozoa is remodelled during ejaculation. Proteins are essential for sperm function, including their fertilizing capacity. Pig spermatozoa, emitted in well-defined ejaculate fractions, vary in their functionality, which could be related to different sperm protein composition. This study aimed (i) to update the porcine sperm proteome and (ii) to identify proteins differentially expressed in mature spermatozoa from cauda epididymis and those delivered in separate ejaculate fractions. Ejaculates from nine mature and fertile boars were manually collected in three separate portions: the first 10 ml of the sperm-rich ejaculate fraction (SRF), the rest of the SRF and the post-SRF. The contents of cauda epididymides of the boars were collected post-mortem by retrograde duct perfusion, generating four different semen sources for each boar. Following centrifugation, the resulting pellets of each semen source were initially pooled and later split to generate two technical replicates per source. The resulting eight sperm samples (two per semen source) were subjected to iTRAQ-based 2D-LC-MS/MS for protein identification and quantification. A total of 1,723 proteins were identified (974 of Sus scrofa taxonomy) and 1,602 of them were also quantified (960 of Sus scrofa taxonomy).After an ANOVA test, 32 Sus scrofa proteins showed quantitative differences (p < 0.01) among semen sources, which was particularly relevant for sperm functionality in the post-SRF. The present study showed that the proteome of boar spermatozoa is remodeled during ejaculation involving proteins clearly implicated in sperm function. The findings provide valuable groundwork for further studies focused on identifying protein biomarkers of sperm fertility.

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Section: Resultsmentioning

confidence: 99%

The Proteome of Pig Spermatozoa Is Remodeled During Ejaculation

Pérez-Patiño

Parrilla

et al. 2019

Molecular & Cellular Proteomics

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“…8 Another known contributor of ROS production in aged animals is Thrombospondin 1 (Thbs-1), which has also been shown to result in deranged vascular reactivity. [9][10][11] A recent study describes Thbs-1 as a novel mediator of IR injury by inducing cellular ROS generation in vascular tissue, but the signaling mechanisms have not been identified. 12 In addition, controlling Drp-1-mediated excessive mitochondrial fission after myocardial ischemia has been shown to contribute to the prevention of long-term cardiac dysfunction.…”

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confidence: 99%

Thrombospondin‐1 mediates Drp‐1 signaling following ischemia reperfusion in the aging heart

et al. 2020

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Ischemia reperfusion (IR) injury leads to activation of dynamin‐related protein (Drp‐1), causing mitochondrial fission and generation of reactive oxygen species (ROS), but the molecular mechanisms that activate Drp‐1 are not known. The purpose of this study was to establish the signaling pathway between Thbs‐1/CD47 and fission protein (Drp‐1) through PGC‐1 following IR in advancing age. Methods Female Fischer‐344 rats were divided into 4 groups: Young Control, Young+IR, Old Control and Old+IR. Echocardiography measurements were done at baseline and 72 hours after IR (30 minutes of ischemia,72 hrs of reperfusion). After evaluation of heart function and coronary flow using vevo3100, hearts were explanted and mitochondrial ROS generation was measured using MitoPY1 (O2·−), as well as protein levels of Thbs‐1, PGC‐1, and Drp‐1. In vitro, rat aortic endothelial cells (RAEC) received hypoxic conditions to mimic IR in vivo model. Cells were treated with SiRNA for PGC‐1 or control scrambled SIRNA and then underwent hypoxia challenge to evaluate PGC‐1 effect on Drp‐1. Cell lysate was collected for Western Blot after 36 hours of transfection. Results Mitochondrial O2·− generation in heart tissue increased in both age groups following IR. Old animals experiencing diastolic dysfunction at the baseline, after IR they exhibited reduced systolic function and exacerbated diastolic dysfunction compared to young controls. IR induces Thbs‐1 and Drp‐1 expression in young and old hearts. SiRNA to PGC‐1 enhanced levels of Drp‐1 in RAECs and increases ROS generation after hypoxia. Conclusion Left ventricular diastolic dysfunction during IR is potentiated due to increased generation of ROS. These results highlight a novel signaling pathway by which Thbs‐1 regulates mitochondrial fission (Drp‐1) and ROS generation during hypoxia, and presumably, following IR. Inhibiting Thbs‐1 immediately after IR may prevent Drp‐1‐mediated mitochondrial fission and is likely to improve diastolic function of the heart by reducing ROS‐mediated cardiomyocyte damage in the aged population. Support or Funding Information NIH R01 AG05358 Gheen's Foundation This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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“…2C), which is discussed in more detail elsewhere in this Forum (34,81,119,124,128,178). We review the emerging physiological functions of this regulation and the evidence that pathological dysregulation of matricellular protein expression contributes to acute and chronic disease states that are characterized by insufficient NO signaling and/or increased oxidative stress.…”

Section: Fig 1 Matricellular Protein Familiesmentioning

confidence: 99%

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

Roberts

Kaur

Isenberg

2017

Antioxidants & Redox Signaling

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Significance: In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors, matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H 2 S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 (TSP1) regulates NO, H 2 S, and superoxide production and signaling in several cell types. The TSP1 receptor CD47 plays a central role in inhibition of NO signaling, but other TSP1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Critical Issues: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. Future Directions: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. Antioxid. Redox Signal. 27, 874-911.

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Thrombospondin-1, Free Radicals, and the Coronary Microcirculation: The Aging Conundrum

Abstract: Current therapies that may effectively disrupt Thbs-1 and its receptor CD47 in the vascular wall and areas for future exploration will be discussed. Antioxid. Redox Signal. 27, 785-801.

Cited by 16 publications

References 169 publications

The Proteome of Pig Spermatozoa Is Remodeled During Ejaculation

The Proteome of Pig Spermatozoa Is Remodeled During Ejaculation

Thrombospondin‐1 mediates Drp‐1 signaling following ischemia reperfusion in the aging heart

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

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