Abstract 5940: Pttg1 Regulates Cardiac Hypertrophy
Genetic Hypertrophic cardiomyopathy (HCM) is the most common identifiable cause of sudden cardiac death. However, the cellular mechanisms are not well known. The triad of HCM is ventricular hypertrophy, myocyte disarray and fibrosis. We demonstrate in the knock out mice for the TGFbeta inducible early gene-1 (TIEG1) the phenotypic characteristics of HCM via upregulation of Pttg1 in the mouse heart and confirmed the upregulation of Pttg1 in Human ex vivo HCM from septal myectomy. The TIEG−/− Mice were characterized age 4 to 16 months (N = 86 total) using echocardiography, transcript profiling by gene microarray, and immunohistochemistry. The female mice (N=40) did not develop the phenotype. Human septal HCM (N=20) were studied. The TIEG−/− null mouse developed features of cardiac hypertrophy including asymmetric septal hypertrophy, an increase in ventricular size at age 16 mo, an increase (214%) in mouse heart/weight body weight ratio TIEG−/− and an increase in wall thickness in TIEG−/− mice of (1.85±0.21 mm), compared to the control (1.13± 0.15 mm, p< 0.04). Masson Trichrome staining demonstrated evidence of myocyte disarray and myofibroblast fibrosis. Microarray analysis of the left ventricles demonstrated that TIEG−/− heart tissues expressed a 13.81 fold increase in pituitary tumor transforming gene, Pttg1. An increase in Pttg1 and Histone H3 protein levels were confirmed in the TIEG−/− mice hearts tissues. Fibrosis was characterized in (N=20) using semi-quantitative RTPCR for bone matrix proteins osteopontin, osteocalcin, osteoblast transcription factors sox9, cbfa1, calcein incorporation for calcification, and immunohistochemistry to assess for evidence of resident cardiac stem cell (CSC) (c-kit) and ostepontin. The null mouse developed increase in all markers including calcification by Synchotron (6-Fold, p<0.05). Human HCM specimens expressed (6-fold, p<0.05) increase in Pttg1 expression by protein and RNA expression and calcification markers. The Pttg1 null mice develop no hypertrophy by echocardiography. We present evidence implicating TIEG and its target gene, Pttg1, in the development of cardiac hypertrophy in the TIEG null mouse and human HCM, implicating a novel regulator of cardiac hypertrophy.
This research has received full or partial funding support from the American Heart Association, AHA National Center.