title: C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response.
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 α-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-κB/p65 (p-p65) in cardiomyocytes, nuclear NF-κB-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, IL-6, GPx3, p47(phox), collagen-I, and transforming growth factor (TGF)-β1, the protein level of TGF-β1, 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.
authors.affiliation: Division of Cardiology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nagai
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Anzai
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Kaneko
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Anzai
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Meguro
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D003251:Constriction, Pathologic; D005355:Fibrosis; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D011312:Pressure; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D015850:Interleukin-6; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; C116888:Gpx3 protein, mouse; D005979:Glutathione Peroxidase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1