scholarly journals Recognition Functions of Pentameric C-Reactive Protein in Cardiovascular Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Alok Agrawal ◽  
Toh B. Gang ◽  
Antonio E. Rusiñol
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Complement Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Host Cells ◽  
Ldl Oxidation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Binding Function

C-reactive protein (CRP) performs two recognition functions that are relevant to cardiovascular disease. First, in its native pentameric conformation, CRP recognizes molecules and cells with exposed phosphocholine (PCh) groups, such as microbial pathogens and damaged cells. PCh-containing ligand-bound CRP activates the complement system to destroy the ligand. Thus, the PCh-binding function of CRP is defensive if it occurs on foreign pathogens because it results in the killing of the pathogen via complement activation. On the other hand, the PCh-binding function of CRP is detrimental if it occurs on injured host cells because it causes more damage to the tissue via complement activation; this is how CRP worsens acute myocardial infarction and ischemia/reperfusion injury. Second, in its nonnative pentameric conformation, CRP also recognizes atherogenic low-density lipoprotein (LDL). Recent data suggest that the LDL-binding function of CRP is beneficial because it prevents formation of macrophage foam cells, attenuates inflammatory effects of LDL, inhibits LDL oxidation, and reduces proatherogenic effects of macrophages, raising the possibility that nonnative CRP may show atheroprotective effects in experimental animals. In conclusion, temporarily inhibiting the PCh-binding function of CRP along with facilitating localized presence of nonnative pentameric CRP could be a promising approach to treat atherosclerosis and myocardial infarction. There is no need to stop the biosynthesis of CRP.

Immunoglobulin M, C-Reactive Protein and Complement Activation in Rat Hepatic Ischemia-Reperfusion Injury

2014 ◽  
Vol 52 (1-2) ◽  
pp. 50-62 ◽  
Author(s):  
Gwendolyn M.P. Diepenhorst ◽  
Wilmar de Graaf ◽  
Hans W. Niessen ◽  
Arlène K. van Vliet ◽  
C. Erik Hack ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Complement Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Immunoglobulin M ◽  
C Reactive Protein ◽  
Hepatic Ischemia ◽  
Reactive Protein ◽  
Hepatic Ischemia Reperfusion

Discovery, in-vitro and in-vivo efficacy of an anti-inflammatory small molecule inhibitor of C-reactive protein

2021 ◽  
Author(s):  
Johannes Zeller ◽  
Karen Cheung Tung Shing ◽  
Tracy Nero ◽  
Guy Krippner ◽  
James McFadyen ◽  
...  
Keyword(s):  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Ischemia ◽  
C Reactive Protein ◽  
Endothelial Cell Activation ◽  
Reactive Protein ◽  
Anti Inflammatory

Abstract C-reactive protein (CRP) is an acute phase protein. We recently identified a novel mechanism that leads to a conformational change from the native, pentameric structure (pCRP) to a pentameric intermediate (pCRP*) and ultimately to the monomeric form, mCRP, both being highly pro-inflammatory. This ‘CRP activation’ is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine (PC) lipid head groups. We designed a low molecular weight pCRP – PC inhibitor, C10M. Binding assays and X-ray crystallography revealed direct, competitive binding of C10M to pCRP, blocking interaction with PC and thereby inhibiting formation of pCRP*/mCRP and their pro-inflammatory effects. The anti-inflammatory potential of C10M was confirmed in-vitro by various measures of leukocyte and endothelial cell activation and in-vivo in rat models of acute ischemia/reperfusion injury and hindlimb transplantation. In conclusion, inhibition of pCRP*/mCRP generation via the PC-mimicking compound C10M represents a promising, potentially broadly applicable anti-inflammatory therapy.

scholarly journals C-reactive protein exacerbates renal ischemia-reperfusion injury

2013 ◽  
Vol 304 (11) ◽  
pp. F1358-F1365 ◽  
Author(s):  
Melissa A. Pegues ◽  
Mark A. McCrory ◽  
Abolfazl Zarjou ◽  
Alexander J. Szalai
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Alternative Activation ◽  
Pcr Analysis ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Renal Ischemia Reperfusion Injury

Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), occurring with hypotension and cardiovascular surgery and inevitably during kidney transplantation. Mortality from AKI is high due to incomplete knowledge of the pathogenesis of IRI and the lack of an effective therapy. Inflammation accompanies IRI and increases the blood level of C-reactive protein (CRP), a biomarker of worsened outcomes in AKI. To test if CRP is causal in AKI we subjected wild-type mice (WT) and human CRP transgenic mice (CRPtg) to bilateral renal IRI (both pedicles clamped for 30 min at 37°C then reperfused for 24 h). Serum human CRP level was increased approximately sixfold after IRI in CRPtg (10.62 ± 1.31 μg/ml at baseline vs. 72.01 ± 9.41 μg/ml at 24 h) but was not elevated by sham surgery wherein kidneys were manipulated but not clamped. Compared with WT, serum creatinine, urine albumin, and histological evidence of kidney damage were increased after IRI in CRPtg mice. RT-PCR analysis of mRNA isolated from whole kidneys of CRPtg and WT subjected to IRI revealed that in CRPtg kidneys 1) upregulation of markers of macrophage classical activation (M1 markers) was blunted, 2) downregulation of markers of macrophage alternative activation (M2 markers) was more robust, and 3) expression of the activating receptor FcγRI was increased. Our finding that CRP exacerbates IRI-induced AKI, perhaps by shifting the balance of macrophage activation and FcγR expression towards a detrimental portfolio, might make CRP a promising therapeutic target for the treatment of AKI.

scholarly journals C-reactive protein-mediated complement activation during acute myocardial infarction in humans

2002 ◽  
Vol 39 ◽  
pp. 322
Author(s):  
Wim K. Lagrand ◽  
Remco Nijmeijer ◽  
Hans W. Niessen ◽  
Cees A. Visser ◽  
Wim T. Hermens ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Complement Activation ◽  
C Reactive Protein ◽  
Reactive Protein

scholarly journals Plasma level of mCRP is linked to cardiovascular disease in antineutrophil  cytoplasmic antibody-associated vasculitis

2020 ◽  
Author(s):  
Kaili Wu ◽  
Qinghui Liang ◽  
Bin-Tao Huang ◽  
Na Ding ◽  
Bowei Li ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Plasma Level ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Age Related Macular Degeneration ◽  
Enzyme Linked Immunosorbent Assay ◽  
Gensini Score ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Age Related

Abstract [Background] C-reactive protein (CRP) has two natural isomers: C-reactive protein pentamer (pCRP) and C-reactive protein monomer (mCRP). The levels of CRP are significantly elevated in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). mCRP not only activates the endothelial cells, platelets, leukocytes, and complements, but also has a proinflammatory structural subtype that can localize and deposit in inflammatory tissues. Thus, it regulates a variety of clinical diseases, such as ischemia/reperfusion (I/R) injury, Alzheimer’s disease, age-related macular degeneration, and cardiovascular disease. We hypothesized that plasma mCRP levels are related to cardiovascular disease in AAV. [Methods] In this cross-sectional study, 37 patients with AAV were assessed. Brain natriuretic peptide (BNP) and mCRP in plasma were assessed by enzyme-linked immunosorbent assay (ELISA). The acute ST-segment elevation myocardial infarction (STEMI) was diagnosed by coronary angiography, and the Gensini score calculated. Echocardiography evaluated the ejection fraction (EF%), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular mass index (LVMI). Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine, age, and gender. [Results] The plasma level of mCRP in AAV was significantly higher than that in healthy volunteers (P<0.001). Then, mCRP and CRP levels were compared with and without STEMI complications in AAV. The plasma level of mCRP was higher, but that of CRP was lower in STEMI. The plasma level of mCRP was correlated with Birmingham vasculitis activity score (BVAS), eGFR, BNP, EF%, LVEDV, LVESV, LVMI, and STEMI complications’ Gensini score in AAV; however, CRP did not correlate with BNP, EF%, LVEDV, LVESV, LVMI, and Gensini score.[Conclusions] The plasma level of mCRP was related to cardiovascular diseases in AAV patients.

scholarly journals S100A8 and S100A9: DAMPs at the Crossroads between Innate Immunity, Traditional Risk Factors, and Cardiovascular Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Alexandru Schiopu ◽  
Ovidiu S. Cotoi
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Increased Risk ◽  
Coronary Events ◽  
Traditional Risk Factors ◽  
Myocardial Ischemia Reperfusion

Amplification of innate immune responses by endogenous danger-associated molecular patterns (DAMPs) promotes inflammation. The involvement of S100A8 and S100A9, DAMPs belonging to the S100 calgranulin family, in the pathogenesis of cardiovascular disease is attracting an increasing amount of interest. S100A8 and S100A9 (also termed MRP8 and MRP14) preferentially form the S100A8/A9 heterodimer (MRP8/14 or calprotectin) and are constitutively expressed in myeloid cells. The levels of circulating S100A8/A9 in humans strongly correlate to blood neutrophil counts and are increased by traditional cardiovascular risk factors such as smoking, obesity, hyperglycemia, and dyslipidemia. S100A8/A9 is an endogenous ligand of toll-like receptor 4 (TLR4) and of the receptor for advanced glycation end products (RAGE) and has been shown to promote atherogenesis in mice. In humans, S100A8/A9 correlates with the extent of coronary and carotid atherosclerosis and with a vulnerable plaque phenotype. S100A8/A9 is locally released following myocardial infarction and amplifies the inflammatory responses associated with myocardial ischemia/reperfusion injury. Elevated plasma levels of S100A8/A9 are associated with increased risk of future coronary events in healthy individuals and in myocardial infarction survivors. Thus, S100A8/A9 might represent a useful biomarker and therapeutic target in cardiovascular disease. Importantly, S100A8/A9 blockers have been developed and are approved for clinical testing.

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