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 ...