Enhanced Integrin Activation of PLD2-Deficient Platelets Accelerates Inflammation after Myocardial Infarction

Klose, Aglaia Maria; Klier, Meike; Gorreßen, Simone; Elvers, Margitta

doi:10.3390/ijms21093210

Cited by 10 publications

(6 citation statements)

References 31 publications

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“…Thus, our study comparing the outcome of AMI under acute and chronic thrombocytopenia in mice provides a first hind for the different results published by different groups. Besides, different results from our group published in the last years indicate that alterations in the inflammatory response alone are not sufficient to effect infarct size or left ventricular function after AMI [ 57 , 58 ]. However, further investigations are necessary to analyze the impact of thrombocytopenia on AMI and to improve the prognosis of patients with AMI and thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

Only Acute but Not Chronic Thrombocytopenia Protects Mice against Left Ventricular Dysfunction after Acute Myocardial Infarction

Reusswig

Polzin

Klier

et al. 2022

Cells

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Background: Platelets are major players of thrombosis and inflammation after acute myocardial infarction (AMI). The impact of thrombocytopenia on platelet-induced cellular processes post AMI is not well defined. Methods: The left anterior descending artery was ligated in C57/Bl6 mice and in two thrombocytopenic mouse models to induce AMI. Results: Platelets from STEMI patients and from C57/Bl6 mice displayed enhanced platelet activation after AMI. This allows platelets to migrate into the infarct but not into the remote zone of the left ventricle. Acute thrombocytopenia by antibody-induced platelet depletion resulted in reduced infarct size and improved cardiac function 24 h and 21 days post AMI. This was due to reduced platelet-mediated inflammation after 24 h and reduced scar formation after 21 days post AMI. The collagen composition and interstitial collagen content in the left ventricle were altered due to platelet interaction with cardiac fibroblasts. Acute inflammation was also significantly reduced in Mpl−/− mice with chronic thrombocytopenia, but cardiac remodeling was unaltered. Consequently, left ventricular function, infarct size and scar formation in Mpl−/− mice were comparable to controls. Conclusion: This study discovers a novel role for platelets in cardiac remodeling and reveals that acute but not chronic thrombocytopenia protects left ventricular function post AMI.

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Section: Discussionmentioning

confidence: 99%

Only Acute but Not Chronic Thrombocytopenia Protects Mice against Left Ventricular Dysfunction after Acute Myocardial Infarction

Reusswig

Polzin

Klier

et al. 2022

Cells

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“…PLD2 is expressed in cardiomyocytes and contributes to the development of several cardiac disorders by regulating inflammatory responses [ 14 ]. However, the involvement of PLD2 in the pathogenesis of SICM remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…It is a key intracellular signaling effector protein required for cellular resistance to microbial invasion and inflammatory responses [ 11 , 12 ]. It primarily localizes to sarcolemmal membranes [ 13 ] and is involved in the development of numerous cardiac disorders such as ischemia–reperfusion damage [ 14 ], congestive heart failure [ 15 ], and cardiac hypertrophy [ 16 ]. However, the role of PLD2 in SICM has not been reported.…”

Section: Introductionmentioning

confidence: 99%

PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway

Li,

Teng,

Jia

et al. 2024

Inflamm. Res.

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Objective Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication. Phospholipase D2 (PLD2) is crucial in mediating inflammatory reactions and is associated with the prognosis of patients with sepsis. Whether PLD2 is involved in the pathophysiology of SICM remains unknown. This study aimed to investigate the effect of PLD2 knockout on SICM and to explore potential mechanisms. Methods The SICM model was established using cecal ligation and puncture in wild-type and PLD2-knockout mice and lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Transfection with PLD2-shRNA lentivirus and a PLD2 overexpression plasmid were used to interfere with PLD2 expression in H9C2 cells. Cardiac pathological alterations, cardiac function, markers of myocardial injury, and inflammatory factors were used to evaluate the SICM model. The expression of pyroptosis-related proteins (NLRP3, cleaved caspase 1, and GSDMD-N) was assessed using western blotting, immunofluorescence, and immunohistochemistry. Results SICM mice had myocardial tissue damage, increased inflammatory response, and impaired heart function, accompanied by elevated PLD2 expression. PLD2 deletion improved cardiac histological changes, mitigated cTNI production, and enhanced the survival of the SICM mice. Compared with controls, PLD2-knockdown H9C2 exhibits a decrease in inflammatory markers and lactate dehydrogenase production, and scanning electron microscopy results suggest that pyroptosis may be involved. The overexpression of PLD2 increased the expression of NLRP3 in cardiomyocytes. In addition, PLD2 deletion decreased the expression of pyroptosis-related proteins in SICM mice and LPS-induced H9C2 cells. Conclusion PLD2 deletion is involved in SICM pathogenesis and is associated with the inhibition of the myocardial inflammatory response and pyroptosis through the NLRP3/caspase 1/GSDMD pathway.

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“…Proteome studies have revealed the presence of DGKZ in human but not mouse platelets, but did not detect PLD2 in the platelets of either species (33,34). Nonetheless, functional studies indicate that human (35) or mouse (36) platelets and in in vitro differentiated mouse MKs (37) express PLD2. The log2 mean expression value of PLD2 was low in all D7 to D14 cell subsets (between 5 and 6); in contrast, DGKZ expression increased 4-fold from D7 to D14 in productive cells, in agreement with its reported presence in platelets (Supplemental Figure 12).…”

Section: The Differential Expression Profiles Point To a Key Regulatory Role Of Mtorcs During Mk Differentiationmentioning

confidence: 99%

Transcriptome analysis of the effect of AHR on productive and unproductive pathways of in vitro megakaryocytopoiesis

Mallo

Sacramento

Gachet

et al. 2021

Preprint

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Human CD34+ progenitors can be differentiated in vitro into proplatelet-producing megakaryocytes (MKs) within 17 days. During this time, four cell populations emerge, phenotypically defined as CD34+CD41+ on day 7 (D7) and CD34+CD41+CD9- on D10 and D14 - qualified as productive because they can differentiate into proplatelet-forming cells during the D14-D17 period - and CD34-CD41+ or CD34+CD41+CD9+ on day 10 - qualified as unproductive because they are unable to form proplatelets later. Coculture with mesenchymal stem cells, or the presence of the AHR antagonist SR1, boosts the productive pathway in two ways: firstly, it increases the yield of D10 and D14 CD34+CD41+CD9- cells and secondly, it greatly increases their ability to generate proplatelets; in contrast, SR1 has no noticeable effect on the unproductive cell types. A transcriptome analysis was performed to decipher the genetic basis of these properties. This work represents the first extensive description of the genetic perturbations which accompany the differentiation of CD34+ progenitors into mature MKs at a subpopulation level. It highlights a wide variety of biological changes modulated in a time-dependent manner and allows anyone, according to his/her interests, to focus on specific biological processes accompanying MK differentiation. For example, the modulation of the expression of genes associated with cell proliferation, lipid and cholesterol synthesis, extracellular matrix components, intercellular interacting receptors and MK and platelet functions reflected the chronological development of the productive cells and pointed to unsuspected pathways. Surprisingly, SR1 only affected the gene expression profile of D10 CD34+CD41+CD9- cells; thus, as compared to these cells and those present on D14, the poorly productive D10 CD34+CD41+CD9- cells obtained in the absence of SR1 and the two unproductive populations present on D10 displayed an intermediate gene expression pattern. In other words, the ability to generate proplatelets between D10 and D14 appeared to be linked to the capacity of SR1 to delay MK differentiation, meanwhile avoiding intermediate and inappropriate genetic perturbations. Paradoxically, the D14 CD34+CD41+CD9- cells obtained under SR1- or SR1+ conditions were virtually identical, raising the question as to whether their strong differences in terms of proplatelet production, in the absence of SR1 and between D14 and D17, are mediated by miRNAs or by memory post-translational regulatory mechanisms.

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Enhanced Integrin Activation of PLD2-Deficient Platelets Accelerates Inflammation after Myocardial Infarction

Cited by 10 publications

References 31 publications

Only Acute but Not Chronic Thrombocytopenia Protects Mice against Left Ventricular Dysfunction after Acute Myocardial Infarction

Only Acute but Not Chronic Thrombocytopenia Protects Mice against Left Ventricular Dysfunction after Acute Myocardial Infarction

PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway

Transcriptome analysis of the effect of AHR on productive and unproductive pathways of in vitro megakaryocytopoiesis

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