Yoshinori Mano

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

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 &agr;-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47phox), and collagen-I, the number of infiltrating Mac-2–positive macrophages, nuclear localization of phosphorylated NF-&kgr;B/p65 (p-p65) in cardiomyocytes, nuclear NF-&kgr;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, IL-6, GPx3, p47phox, collagen-I, and transforming growth factor (TGF)-&bgr;1, the protein level of TGF-&bgr;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.

Increased C-reactive protein expression exacerbates left ventricular dysfunction and remodeling after myocardial infarction.

We previously reported serum C-reactive protein (CRP) elevation after acute myocardial infarction (MI) to be associated with adverse outcomes including cardiac rupture, left ventricular (LV) remodeling, and cardiac death. Experimental studies have indicated that CRP per se has various biological actions including proinflammatory and proapoptotic effects, suggesting a pathogenic role of CRP in the post-MI remodeling process. We tested the hypothesis that increased CRP expression would exacerbate adverse LV remodeling after MI via deleterious effects of CRP. Transgenic mice with human CRP expression (CRP-Tg) and their transgene-negative littermates (control) underwent left coronary artery ligation. There was no apparent difference in phenotypic features between CRP-Tg and control mice before MI. Although mortality and infarct size were similar in the two groups, CRP-Tg mice showed more LV dilation and worse LV function with more prominent cardiomyocyte hypertrophy and fibrosis in the noninfarcted regions after MI than controls. Histological evaluation conducted 1 wk post-MI revealed a higher rate of apoptosis and more macrophage infiltration in the border zones of infarcted hearts from CRP-Tg mice in relation to increased monocyte chemotactic protein (MCP)-1 expression and matrix metalloproteinase (MMP)-9 activity. Increased CRP expression exacerbates LV dysfunction and promotes adverse LV remodeling after MI in mice. The deleterious effect of CRP on post-MI LV remodeling may be associated with increased apoptotic rates, macrophage infiltration, MCP-1 expression, and MMP-9 activity in the border zone.

Prognostic Significance of Acute Kidney Injury After Reperfused ST-Elevation Myocardial Infarction: Synergistic Acceleration of Renal Dysfunction and Left Ventricular Remodeling

BACKGROUND Acute kidney injury (AKI) after myocardial infarction is associated with poor clinical outcome. However, mechanisms of the adverse effect of AKI on clinical outcome after reperfused ST-elevation myocardial infarction (STEMI) have not been fully elucidated. METHODS AND RESULTS We examined 141 consecutive patients with reperfused first anterior STEMI. AKI was defined as an increase in serum creatinine of >or=0.3mg/dL within 48hours after admission. Patients with AKI had higher incidence of in-hospital cardiac death (P=.0004) and major adverse cardiac events (MACE, P=.020) during a mean of 39+/-40 (range, 1 to 96) months than those without, in association with adverse left ventricular (LV) remodeling. White blood cell count on admission and peak C-reactive protein were higher in patients with than those without AKI. Plasma norepinephrine on admission, interleukin-6, brain natriuretic peptide, and malondialdehyde-modified low-density lipoprotein 2 weeks after STEMI were higher in patients with AKI than those without AKI. Cox proportional hazards model analysis revealed AKI was an independent predictor of MACE (hazard ratio=2.38, P=.019). CONCLUSIONS AKI was a strong predictor of MACE in association with adverse LV remodeling. Enhanced inflammatory response, oxidative stress, and neurohormonal activation may synergistically accelerate renal dysfunction and LV remodeling after STEMI.

Eicosapentaenoic acid suppresses adverse effects of C-reactive protein overexpression on pressure overload-induced cardiac remodeling

Serum C-reactive protein (CRP) elevation is associated with poor clinical outcome in patients with heart failure (HF). We previously reported that CRP exacerbates the development of pressure overload-induced cardiac remodeling through an enhanced inflammatory response and oxidative stress. In the present study, we examined the effect of eicosapentaenoic acid (EPA), a suppressor of inflammatory response and oxidative stress, on pressure overload-induced cardiac remodeling. Transverse aortic constriction (TAC) was performed on transgenic mice overexpressing CRP (CRPtg) and nontransgenic littermates (TAC/CON). CRPtg with TAC operation were randomly assigned to be fed a standard diet (TAC/CRPtg) or an EPA-enriched diet (7 % of total energy) (TAC/CRPtg/EPA). Myocardial mRNA level of transforming growth factor-β1, proinflammatory cytokines, and oxidative stress markers were increased in TAC/CRPtg in comparison with TAC/CON 1 and 4 weeks after the operation. These parameters were significantly suppressed in TAC/CRPtg/EPA compared with TAC/CRPtg. In addition, after 4 weeks of EPA treatment, as compared with TAC/CRPtg, TAC/CRPtg/EPA mice demonstrated reduced heart and lung weights, increased left ventricular fractional shortening, and decreased left ventricular end-diastolic pressure, together with decreased cardiac hypertrophy, fibrosis, and improved cardiac function. In conclusion, the anti-inflammatory and antioxidative properties of EPA may make it an effective therapeutic strategy for adverse cardiac remodeling associated with CRP overexpression.