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

ABSTRACT: BACKGROUND:Phospholipase (PL)D1 is crucial for integrin ?IIb?3 activation of platelets in arterial thrombosis and TNF-?-mediated inflammation and TGF-?-mediated collagen scar formation after myocardial infarction (MI) in mice. Enzymatic activity of PLD is not responsible for PLD-mediated TNF-? signaling and myocardial healing. The impact of PLD2 in ischemia reperfusion injury is unknown. METHODS:PLD2-deficient mice underwent myocardial ischemia and reperfusion (I/R). RESULTS:Enhanced integrin ?IIb?3 activation of platelets resulted in elevated interleukin (IL)-6 release from endothelial cells in vitro and enhanced IL-6 plasma levels after MI in PLD2-deficient mice. This was accompanied by enhanced migration of inflammatory cells into the infarct border zone and reduced TGF-? plasma levels after 72 h that might account for enhanced inflammation in PLD2-deficient mice. In contrast to PLD1, TNF-? signaling, infarct size and cardiac function 24 h after I/R were not altered when PLD2 was deleted. Furthermore, TGF-? plasma levels, scar formation and heart function were comparable between PLD2-deficient and control mice 21 days post MI. CONCLUSIONS:The present study contributes to our understanding about the role of PLD isoforms and altered platelet signaling in the process of myocardial I/R injury.

SUBMITTER: Klose AM

PROVIDER: S-EPMC7247352 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Klose Aglaia Maria AM Klier Meike M Gorressen Simone S Elvers Margitta M

International journal of molecular sciences 20200501 9

<h4>Background</h4>Phospholipase (PL)D1 is crucial for integrin α<sub>IIb</sub>β<sub>3</sub> activation of platelets in arterial thrombosis and TNF-α-mediated inflammation and TGF-β-mediated collagen scar formation after myocardial infarction (MI) in mice. Enzymatic activity of PLD is not responsible for PLD-mediated TNF-α signaling and myocardial healing. The impact of PLD2 in ischemia reperfusion injury is unknown.<h4>Methods</h4>PLD2-deficient mice underwent myocardial ischemia and reperfusio ...[more]

PMID: 32370031

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Project description:Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication Disruptions of systemic homeostasis have emerged as critical regulators of cancer. Recent studies indicate that chronic or acute host stressors (e.g., obesity1, surgery2) alter cancer pathogenesis. Many cancer patients, particularly those with breast cancer, are at increased risk for cardiovascular disease due to treatment toxicity and resulting changes in lifestyle behaviors3-5. While elevated risk and incidence of cardiovascular events in breast cancer is well-established, whether such events impact cancer pathogenesis is not known. Herein, we show that an incident myocardial infarction (MI or heart attack) accelerates breast cancer outgrowth and cancer-specific mortality in mice and humans. In mouse models of breast cancer, MI epigenetically reprogrammed Ly6Chigh monocytes in the bone marrow reservoir to an immunosuppressive phenotype that was maintained at the transcriptional level in monocytes in the circulation and tumor. In parallel, MI increased circulating Ly6Chigh monocyte levels and recruitment to tumors, and depletion of these cells abrogated MI-induced tumor growth. Furthermore, evaluation of the relationship between a new onset post-diagnosis cardiovascular event and cancer outcomes in early-stage breast cancer patients revealed increased risk of recurrence and cancer-specific death, highlighting the clinical relevance of our findings. Collectively, our results demonstrate that MI induces alterations to systemic homeostasis, triggering cross-disease communication that accelerates breast cancer.

Dataset Information

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

Publications

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

Similar Datasets

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