C-Reactive Protein Overexpression Exacerbates Pressure Overload–Induced Cardiac Remodeling Through Enhanced Inflammatory Response

Abstract

Abstract-Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload-induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa ␣-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47 phox ), and collagen-I, the number of infiltrating Mac-2-positive macrophages, nuclear localization of phosphorylated NF-B/p65 (p-p65) in cardiomyocytes, nuclear NF-B-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, GPx3, p47 phox , collagen-I, and transforming growth factor (TGF)-␤1, the protein level of TGF-␤1, and the numbers of Mac-2-positive macrophages and p-p65-positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload-induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress. C -reactive protein (CRP), which is an acute-phase protein, has been regarded as a risk factor or biomarker for cardiovascular disease, including coronary artery disease, hypertension, and heart failure. Elevation of serum CRP is associated with left ventricular (LV) dysfunction and is a predictor of mortality and morbidity in patients with heart failure, independent of ischemic/nonischemic etiology and other established cardiovascular risk factors. 1-3 Laboratory evidence suggests that CRP not only serves as a biomarker but also upregulates the angiotensin type 1 receptor (AT 1 R), 4 stimulates proinflammatory cytokine production, 5 and attenuates nitric oxide (NO) production. 6 In addition, pathological examination of endomyocardial biopsies in patients with dilated cardiomyopathy revealed that CRP is frequently present in the myocardium and colocalizes with complement and macrophages. 7 Furthermore, CRP is reported to promote fibrosis and inflammation in angiotensin II-induced cardiac remodeling. 8 These findings suggest that CRP itself may play some role in the development of LV dysfunction and remodeling.Human CRP is mainly produced in the ...

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C-reactive protein (CRP) gene polymorphisms, CRP levels and risk of incident essential hypertension: findings from an observational cohort of Han Chinese

“…Nagai et al 26 showed that transgenic transverse aortic constriction mice overexpressing the human CRP gene had higher myocardial messenger RNA levels of interleukin-6, CD68 and collagen-I, and greater levels of infiltrating Mac-2-positive macrophages and reactive oxygen species than nontransgenic  transverse aortic constriction mice. At 4 weeks after surgery, the heart and lung weights and extent of cardiac fibrosis were greater in transgenic transverse aortic constriction mice.…”

Left Ventricular Remodeling after Acute Myocardial Infarction and Biomarkers

“…These findings suggest that CRP itself may play some role in the development of LV dysfunction and remodeling [9].…”

“…Increased level of CRP is associated with left ventricular (LV) dysfunction and demonstrate higher mortality and morbidity risk in patients with heart failure. It is an independent factor of ischemic or non-ischemic etiology and other cardiovascular risk factors [9]. CRP is reported to promote fibrosis and inflammation in angiotensin II induced myocardial remodeling [10].…”