Blockade of NKG2D/NKG2D ligand interaction attenuated cardiac remodelling after myocardial infarction

Matsumoto, Kotaro; Obana, Masanori; Kobayashi, Ai; Kihara, Miho; Shioi, Go; Miyagawa, Shigeru; Maeda, Makiko; Sakata, Yasushi; Nakayama, Hiroyuki; Sawa, Yoshiki; Fujio, Yasushi

doi:10.1093/cvr/cvy254

Cited by 11 publications

(9 citation statements)

References 35 publications

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“…3 a1–a3). Cardiomyocytes are susceptible to apoptosis during MI (Matsumoto et al 2019 ). Gastrin has been reported to protect cells from apoptosis (Ramamoorthy et al 2004 ) and promote cell proliferation (Duckworth et al 2013 ).…”

Section: Resultsmentioning

confidence: 99%

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

Tang

Zhang

et al. 2021

Mol Med

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Background It is known that increased gastrin concentration is negatively correlated with cardiovascular mortality, and plasma gastrin levels are increased in patients after myocardial infarction (MI). However, whether gastrin can play a protective role in MI remains unknown. Methods Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery (LAD) and subcutaneous infusion of gastrin (120 μg/Kg body weight/day, 100 μL in the pump) for 28 days after MI. Plasma gastrin concentrations were measured through an ELISA detection kit. Mice were analyzed by echocardiography after surgery. CD31 and VEGF expression were quantified using immunofluorescence staining or/and western blot to assess the angiogenesis in peri-infarct myocardium. Capillary-like tube formation and cell migration assays were performed to detect gastrin-induced angiogenesis. Results We found that gastrin administration significantly ameliorated MI-induced cardiac dysfunction and reduced fibrosis at 28 days in post-MI hearts. Additionally, gastrin treatment significantly decreased cardiomyocyte apoptosis and increased angiogenesis in the infarct border zone without influencing cardiomyocyte proliferation. In vitro results revealed that gastrin up-regulated the PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway and promoted migration and tube formation of human coronary artery endothelial cells (HCAECs). Cholecystokinin 2 receptor (CCK2R) mediated the protective effect of gastrin since the CCK2R blocker CI988 attenuated the gastrin-mediated angiogenesis and cardiac function protection. Conclusion Our data revealed that gastrin promoted angiogenesis and improved cardiac function in post-MI mice, highlighting its potential as a therapeutic target candidate.

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Section: Resultsmentioning

confidence: 99%

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

Tang

Zhang

et al. 2021

Mol Med

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“…First, we noted an activation signature in NK cells with dysregulation of the activating receptor NKG2D, possibly linked to vaccine-associated myopericarditis. NKG2D is an activating receptor that binds stress ligands on tissues, including the heart (88), inducing cytotoxic effector responses (89)(90)(91)(92)(93)(94)(95)(96). Elevation and activation of NK cells were also reported in two patients with vaccine-associated myocarditis/myopericarditis from different studies (32,40).…”

Section: Discussionmentioning

confidence: 98%

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis

et al. 2023

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Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2–specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1β, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3 + cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2 + CD163 + monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell–associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine–-associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.

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“…It is possible that mtDNA indirectly activates RAE-1 expression that is involved in cardiac fibrosis and remodeling in the remodeling phase. 50,51 Normally, extracellular mtDNA originates from various sources, including in the formation of neutrophil extracellular traps or from platelets. 52,53 However, in the pro-inflammatory phase after ischemia-reperfusion injury, most extracellular mtDNA originates from necrotic cardiomyocytes and elevated levels of mtDNA has been found in circulation of myocardial infarction patients.…”

Section: Mitochondrial Dnamentioning

confidence: 99%

“…Ischemia‐injured cardiomyocytes show increased expression of retinoic acid early transcript 1 (RAE‐1) in the early phase after ischemia, which is thought to be activated through the STING pathway. It is possible that mtDNA indirectly activates RAE‐1 expression that is involved in cardiac fibrosis and remodeling in the remodeling phase 50,51 …”

Section: Mitochondria‐derived Damps In Cardiac Inflammatory Signalingmentioning

confidence: 99%

Mitochondria‐derived damage‐associated molecular patterns and inflammation in the ischemic‐reperfused heart

2023

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Cardiac cell death after myocardial infarction release endogenous structures termed damage‐associated molecular patterns (DAMPs) that trigger the innate immune system and initiate a sterile inflammation in the myocardium. Cardiomyocytes are energy demanding cells and 30% of their volume are mitochondria. Mitochondria are evolutionary endosymbionts originating from bacteria containing molecular patterns similar to bacteria, termed mitochondrial DAMPs (mDAMPs). Consequently, mitochondrial debris may be particularly immunogenic and damaging. However, the role of mDAMPs in myocardial infarction is not clarified. Identifying the most harmful mDAMPs and inhibiting their early inflammatory signaling may reduce infarct size and the risk of developing post‐infarct heart failure. The focus of this review is the role of mDAMPs in the immediate pro‐inflammatory phase after myocardial infarction before arrival of immune cells in the myocardium. We discuss different mDAMPs, their role in physiology and present knowledge regarding their role in the inflammatory response of acute myocardial infarction.

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Blockade of NKG2D/NKG2D ligand interaction attenuated cardiac remodelling after myocardial infarction

Cited by 11 publications

References 35 publications

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine–associated myocarditis

Mitochondria‐derived damage‐associated molecular patterns and inflammation in the ischemic‐reperfused heart

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