Abstract 149: Effect of Pentraxin 3 on Pressure Overload--Induced Left Ventricular Hypertrophy

Abstract

Backgrounds: Left ventricular (LV) adverse remodeling is enhanced by inflammatory cytokines. Pentraxin 3 (PTX3), which is one of the pentraxin superfamily same as C-reactive protein, is rapidly produced in response to inflammatory signals, and plasma PTX3 levels are increased in patients with heart failure. Previously we reported that PTX3 deficient mice demonstrated the suppression of hypertrophic cardiac remodeling after pressure overload. This study aimed to examine the cardiac specific influence of PTX3 on LV hypertrophy and dysfunction in response to pressure overload. Methods and Results: We created transgenic (TG) mice with cardiac-specific overexpression of PTX3 using alpha-myosin heavy chain promoter. We performed transverse aortic constriction (TAC) or sham operation on TG and wild type (WT) littermate mice. Expression of PTX3 was increased after TAC in WT mice, and immunohistochemistry proved that PTX3 was produced mainly from the interstitial tissue of the heart and infiltrating macrophages. Activation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa-B was enhanced in TG mice compared to WT mice after TAC. Interleukin-6 production in heart tissue was augmented in TG mice compared to WT mice. Echocardiography and cardiac catheterization revealed that adverse remodeling with LV dysfunction was enhanced with increased interstitial fibrosis in TG mice compared to WT mice. Real time RT-PCR demonstrated that gene expressions related to cardiac hypertrophy and fibrosis were augmented in TG mice compared to WT mice. Next we isolated neonatal rat cardiomyocytes and fibroblasts. PTX3 expressions were increased after H 2 O 2 stimulation in cardiomyocytes and fibroblasts. Phosphorylation of ERK by recombinant PTX3 stimulation was more potent in cardiac fibroblasts than in cardiomyocytes. Conclusions: The local inflammatory mediator PTX3 directly modulates the hypertrophic response and LV dysfunction following increased afterload, and cardiac fibroblast might be important target cells of PTX3 stimulation.