The role of complement C3 in the outcome of regional myocardial infarction

Fang, Zhou; Li, Xiang; Liu, Junying; Lee, Haekyung; Salciccioli, Louis; Lazar, Jason; Zhang, Ming

doi:10.1016/j.bbrep.2023.101434

Cited by 5 publications

(11 citation statements)

References 65 publications

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“…Thus, these results confirmed that myocardial apoptosis is increased in C3 -/mice after 60 minutes of heart ischemia followed by 24 hrs of reperfusion. Taken together with our earlier report [13], these findings imply that in WT mice during myocardial I/R, C3 acts to promote necrosis and block apoptosis in heart.…”

Section: Myocardial Apoptosis Is Increased In C3 -/Mice After Heart I/rsupporting

confidence: 89%

“…1 is not due to an increase in the amount of cytochrome c released into the cytosol, but to the genetic lack of C3 available for binding to cytochrome c. It is possible that binding of C3 to cytosolic cytochrome c in WT mice sequesters cytochrome c, thus reducing the number of cells which complete apoptosis. The result from our recent report indicates that necrosis is favored in WT mice expressing C3 [13]. Therefore, during I/R, based on our results, C3 minimizes apoptosis and promotes necrosis.…”

Section: Similar Levels Of Cytochrome C In Myocardial Cytosol Of C3 -...supporting

confidence: 78%

“…Previous animal studies by us and others showed that under pathological conditions such as I/R injury, circulation C3 was deposited in the ischemic myocardium flooded with oxygenated blood upon reperfusion [11,12]. Recently we reported that in the mouse heart model, myocardial necrosis was decreased in C3 −/− mice [13]. This implied that in WT mice during I/R, C3 acts to promote necrosis.…”

Section: Introductionmentioning

confidence: 96%

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Complement C3 interacts with cytochromecto influence myocardial apoptosis during heart ischemia/reperfusion

Fang

Lee

Liu

et al. 2023

Preprint

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Myocardial ischemia/reperfusion (I/R) elicits an acute inflammatory response involving complement factors. Previous animal studies showed that circulation complement C3 was deposited in the ischemic myocardium flooded with oxygenated blood upon reperfusion. Recently, we reported that myocardial necrosis was decreased in C3-/- mice after heart I/R. The current study used in the same heart model to test the effect of C3 on myocardial apoptosis. Our results showed that myocardial apoptosis was increased in C3-/- mice after heart I/R. Further, comparative proteomics analyses found that cytochrome c was present in the myocardial C3-complex following I/R. These results indicate that C3 can interact with cytochrome c in the cytosol of cardiomyocytes during myocardial I/R, which may sequester cytochrome c and thus reduce the number of cells undergoing apoptosis. In summary, our findings raise the possibility of a new mechanism affecting cell death relevant to pathologic conditions such as ischemia: a circulating innate immune factor, i.e. complement, can interact with intracellular factor(s), and influence the types of cell death that occur.

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Section: Myocardial Apoptosis Is Increased In C3 -/Mice After Heart I/rsupporting

confidence: 89%

Section: Similar Levels Of Cytochrome C In Myocardial Cytosol Of C3 -...supporting

confidence: 78%

Section: Introductionmentioning

confidence: 96%

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Complement C3 interacts with cytochromecto influence myocardial apoptosis during heart ischemia/reperfusion

Fang

Lee

Liu

et al. 2023

Preprint

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“…30 This in ammation-mediated response results in cell death of the ischemic tissue and subsequent long-term consequences such as postinfarction heart failure with the hallmarks of cardiac brosis and heart dysfunction. 31 In the present study, the strong correlations between eGC impairment and the elevated levels of CRP, leukocyte count, and elevation of the complement anaphylatoxins indicate a proin ammatory response. The process of eGC shedding is further underpinned by elevated levels of the eGC components (syndecan-1, heparan sulfate, and hyaluronic acid) measured in the STEMI sera, indicating elevated levels of MMPs, and by the strong correlation between eGC height and stiffness (r = .918).…”

Section: Discussionsupporting

confidence: 53%

Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock

Vahldieck

Fels

Löning

et al. 2023

Preprint

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Background Damage to the endothelial glycocalyx (eGC) and endothelial dysfunction have been reported to develop during cardiac ischemia-and-reperfusion injury (IRI), such as ST-elevation myocardial infarction (STEMI). For patients with acute ischemic syndromes and cardiogenic shock a door-to-balloon time (D2B) < 60 min with rapid revascularization was shown to reduce both mortality and nonfatal complications. Here, we hypothesize that prolonged D2B is associated with an unfavorable outcome for the eGC of patients with STEMI. Methods Data of 126 individuals were analyzed in this study. Sixty-three STEMI patients with cardiogenic shock in the event of STEMI were included. All received revascularization through primary percutaneous coronary intervention (PCI). 63 age- and sex-matched healthy volunteers served as controls. After stimulating endothelial cells with patient sera, the nanomechanical properties of the eGC were analyzed using the atomic force microscopy-based nanoindentation technique. Serum levels of eGC components as well as complement anaphylatoxins and angiopoetin-2 were measured via ELISA. Nitric oxide (NO) levels were determined chemiluminescence-based. Results eGC height and stiffness (both, p < 0.001) as well as NO concentration (p < 0.001) were reduced after STEMI. Longer D2B led to significantly higher amounts of eGC components (syndecan-1: 35.5 vs. 136.7 ng/ml; p < 0.001 / heparan sulfate: 4.6 vs. 10.8 ng/ml; p < 0.001 / hyaluronic acid: 116.7 vs. 182.9 µg/ml; p < 0.0001) and troponin-t (p < 0.01) in the patient sera. Notably, D2B had a strong impact on patient outcome. D2B > 60 min led to pronounced loss of eGC height and stiffness (both, p < 0.001), activated the complement system (p < 0.001), and prolonged the hospital stay (p < 0.01) compared to D2B ≤ 60 min. Conclusion Increased D2B led to severe eGC shedding and endothelial dysfunction in a temporal context. In addition, levels of syndecan-1 and proinflammatory mediators correlated with prolonged D2B, indicating a time-dependent immune reaction during cardiogenic shock with increased IRI to the eGC and prolonged hospitalization. D2B therefore appears to be a crucial factor for endothelial IRI in the case of STEMI with cardiogenic shock. Combining the clinical evaluation of the eGC condition with levels of biomarkers such as syndecan-1 might serve as important predictor for eGC impairment of STEMI patients with cardiogenic shock in the future.

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“…Previous animal studies by us and others showed that under pathological conditions such as I/R injury, circulation C3 was deposited in the ischemic myocardium flooded with oxygenated blood upon reperfusion [ 34 , 35 ]. We recently reported that in the mouse heart model, myocardial necrosis was decreased in C3 −/− mice [ 36 ]. This implied that in WT mice during I/R, C3 acts to promote necrosis.…”

Section: Introductionmentioning

confidence: 99%

Complement C3 Reduces Apoptosis via Interaction with the Intrinsic Apoptotic Pathway

Fang,

Lee,

Liu

et al. 2023

Cells

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Myocardial ischemia/reperfusion (I/R) elicits an acute inflammatory response involving complement factors. Recently, we reported that myocardial necrosis was decreased in complement C3−/− mice after heart I/R. The current study used the same heart model to test the effect of C3 on myocardial apoptosis and investigated if C3 regulation of apoptosis occurred in human cardiomyocytes. Comparative proteomics analyses found that cytochrome c was present in the myocardial C3 complex of WT mice following I/R. Incubation of exogenous human C3 reduced apoptosis in a cell culture system of human cardiomyocytes that did not inherently express C3. In addition, human C3 inhibited the intrinsic apoptosis pathway in a cell-free apoptosis system. Finally, human pro-C3 was found to bind with an apoptotic factor, pro-caspase 3, in a cell-free system. Thus, we present firsthand evidence showing that C3 readily reduces myocardial apoptosis via interaction with the intrinsic apoptotic pathway.

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The role of complement C3 in the outcome of regional myocardial infarction

Cited by 5 publications

References 65 publications

Complement C3 interacts with cytochromecto influence myocardial apoptosis during heart ischemia/reperfusion

Complement C3 interacts with cytochromecto influence myocardial apoptosis during heart ischemia/reperfusion

Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock

Complement C3 Reduces Apoptosis via Interaction with the Intrinsic Apoptotic Pathway

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