Research has found that atherosclerosis (AS) is not just the deposition of lipids on the blood vessel wall, but a chronic inflammatory response process. Prospective studies have determined that CRP is an important factor in the existence and future of CVD. independent predictors of occurrence. The application of latex-enhanced agglutination immunoturbidimetry to measure CRP can detect lower levels of CRP, that is, high sensitivity CRP (hs-CRP). CRP levels are positively correlated with waist circumference and body mass index (BMI). In addition, CRP levels in smokers are significantly higher than those in non-smokers. CRP has become an important predictive indicator of CVD. CRP predicts the occurrence of CVD independently of other traditional predictors. These traditional indicators include hypertension, diabetes, hyperlipidemia, smoking, obesity, etc. Moreover, hs-CRP and total cholesterol The combination of HDL/HDL cholesterol ratio is a stronger predictor of CVD than either factor alone.
Multivariate analysis showed that CRP is an independent predictor of cardiovascular mortality in patients with acute decompensated heart failure, suggesting that inflammation is an important component of the pathophysiology of this disease. hs-CRP can not only predict the future trend of CVD in elderly women with subclinical CVD symptoms, but also predict the high risk of CVD in middle-aged men in the next 6 to 7 years, even for seemingly healthy individuals. Predict future risk of CVD. hs-CRP concentration predicts the progression of AS independently of traditional risk factors. Therapeutic strategies to reduce CRP levels and inhibit the inflammatory response can prevent the progression of AS and thereby prevent the occurrence of CVD. CRP levels greater than 15 mg/L are a strong predictor of disease progression within 90 days in patients with unstable angina. Morrow et al. found that patients with CRP levels below 10 mg/L and negative troponin had a mortality rate close to 0 in 24 years of follow-up, while patients with negative troponin and high levels of CRP had a significantly higher mortality rate. When the CRP level is greater than 15.5 mg/I, the mortality rate in patients with unstable angina and non-ST-segment elevation myocardial infarction increases by 18 times. Among European high-risk groups for CVD, men have higher hs-CRP levels than women, while under normal circumstances, women have higher hs-CRP levels than men. The ability of hs-CRP to predict CVD depends on BMI for women and waist circumference for men; the highest hs-CRP levels are mainly seen in patients with both high BMI and waist circumference. Differences in CRP levels do not explain the risk of CVD in Europeans.
Although CRP is supported by many scholars as a predictor of the occurrence of CVD, there is still a lot of evidence that elevated CRP is involved in the formation of arterial plaques and directly leads to CVD, or is simply a very sensitive indicator of inflammation. controversy. The use of apolipoprotein-E-deficient transgenic mice to study human CRP provides direct evidence that CRP is involved in arterial damage. In CVD, CRP accelerates the progression of AS by promoting the uptake of low-density lipoprotein by macrophages, which promotes the inner wall of the artery. Lipid deposition leads to thrombosis. In addition, CRP binds to FcTR on vascular endothelial cells, promoting the expression of cell adhesion molecules, monocyte chemoattractant protein-1, endothelin-1, IL-8, and plasminogen activator inhibitor. The cells infiltrating in the AS inflammation site are mainly macrophages and T lymphocytes. The increased expression of monocyte chemoattractant protein-1 promotes the proliferation, activation, migration and adhesion of monocytes to vascular endothelial cells, and activates The interaction of macrophages with vascular endothelial cells and smooth muscle cells induces the production of matrix-degrading enzymes, which rupture atheromatous plaques by decomposing the fibrous cap. Activated macrophages can also secrete vasoactive substances and coagulation molecules. Constrict blood vessels and form thrombus. In addition, CRP also has a positive chemotactic effect on monocytes like monocyte chemoattractant protein-1, and can induce the production of inflammatory cytokines and promote the expression of tissue factor. Studies have found that CRP can bind to nuclear antigens, including nuclear chromatin, nucleosomes, etc.
CRP can promote the phagocytosis of nuclear antigens by macrophages, affecting the presentation of antigens and masking self-antigens from being recognized by the immune system. In addition, CRP can also promote the clearance of self-antigens by binding to FcTR, which may prevent autoimmune responses and inhibit the occurrence of certain autoimmune diseases.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that manifests as multi-organ involvement. SLE patients have a variety of autoantibodies targeting cytoplasmic and cell surface antigens. Siowall et al. reported that even in patients with SLE who are in the active stage of the disease, their serum CRP levels are generally very low, while the levels of other acute-phase proteins are very high, such as IL-6, the main inducing factor that promotes CRP production. The important role of CRP in autoimmune diseases is to act as an opsonin, promoting the clearance of apoptotic cells, such as nucleosomes, thereby preventing the body's immune response to self-antigens.
Many scholars believe that SLE is an autoimmune response caused by endogenous nuclear antigens released by dying cells. This hypothesis is based on the characteristics of autoantibodies that respond to nuclear chromatin and is based on the response to apoptotic cells. Recognition of abnormal epitopes of self-antigens and clearance of apoptotic cells. In addition to clearing nuclear chromatin, CRP can also bind to apoptotic cells. CRP promotes the phagocytosis of apoptotic cells by macrophages through complement-dependent opsonization, thus having anti-inflammatory effects.
MRL/lpr mice are important animal models of human SLE. These mice exhibit high titers of anti-double-stranded DNA antibodies, immune complex-mediated glomerulonephritis, lymphadenopathy, etc. Marnell et al. found that injecting CRP into MRL/Ipr mice before they develop proteinuria can delay the progression of the disease, and injecting CRP after they develop proteinuria can also make the proteinuria disappear. It can be seen that CRP plays an anti-inflammatory role in these animal models. It is also worth mentioning that there is no correlation between blood URP levels and IL-6 in SLE patients, while serum CRP levels in healthy people are highly positively correlated with serum IL-6.
Interleukin-10 (IL-10) is a cytokine with anti-inflammatory activity. CRP can promote the synthesis of IL-10. Increased IL-10 helps control the immune system's response to self-antigens, thereby inhibiting damage to the host. In a mouse model of IL-10-deficient cytotoxic glomerulonephritis, CRP did not prevent or reduce urinary protein, suggesting that the anti-inflammatory activity of CRP may be mediated by IL-10. CRP The receptor protein (cAMP Receptor Protein, CRP; also known as Catabolite gene activator protein, CAP) in bacteria specifically binds to change the conformation of CRP and activate it. There are three important sites on CRP involved in the gene transcription activation process: the carboxy-terminal binding region (aCTD) with the a subunit of RNA pol, the amino-terminal binding region (aNTD) with the a subunit, and the binding region with the s subunit. . CRP binds to DNA in the form of a dimer and acts as a dimer. The dimer can be activated by a single cAMP. The CRP monomer includes a DNA-binding domain and a transcriptional activation domain.
CRP dimer binds approximately 22 bp sequence
5'-AAATGTGATCTAGATCACATTT-3'
3'-TTTACACTAGATCTAGTGTAAA-5'
The binding of CRP can bend DNA to 90°, and the bending of the binding site can be detected by electrophoretic mobility
In different operons, CRP may act in three different ways.
In the Lac operon, CRP binds upstream of the RNA pol binding site immediately adjacent to the promoter, interacts with aCTD, and interacts with the b and s subunits at the same time.
In the gal operon, the CRP-binding region overlaps with the RNA pol-binding region, and it interacts with aCTD, aNTD and s subunits.
CRP may have two or more dimers bound to different sites on DNA in some operons. For example, in the ara operon, CRP bound to two different sites plays a role. .
CRP activated by cAMP can specifically bind to the CRP site upstream of the promoter of the lac operon. Facilitates the formation of the transcription initiation complex and enhances the activity of RNA polymerase. To express lac operon.
When glucose is present, the cAMP concentration decreases, CRP cannot be activated, and the expression of the 1ac operon decreases. Since P1ac is a weak promoter, it is derepressed only by the presence of lactose, resulting in a very low open expression level of the 1ac operon; with CRP to enhance the transcriptional activity, bacteria can synthesize enough enzymes to utilize lactose