Guy Salama

University of Pittsburgh, United States

Title: Effects of Relaxin on the aged heart

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Biography

Dr. Guy Salama is a Professor within the Department of Medicine, Division of Cardiology at the University of Pittsburgh School of Medicine.  Dr. Salama holds a BS in Physics (1968) from the City College of New York and a MS in Physics (1971) from the University of Pennsylvania. In 1997, he was awarded his PhD in Biochemistry and Biophysics from the University of Pennsylvania. Currently, at the University of Pittsburgh, Dr. Salama is actively involved in both academics and research, and has focused his efforts on the elucidation of the mechanisms responsible for the initiation and termination of cardiac arrhythmias. Dr. Salama first arrived at the university as an Assistant Professor within the Department of Physiology in 1980. By 1987, he was an Associate Professor within the department, and by 1995 he was an Associate Professor within the Department of Cell Biology and Physiology. In 1999, he was appointed to the position of Professor within the Department of Cell Biology and Physiology. Throughout his career, Dr. Salama has been a member of several professional and scientific societies. Currently, he resides as a member of the Biophysical Society, Marine Biological Laboratory (member of the corporation), and the Basic Science Council of the American Heart Association.  He is also a Fellow of the American Heart Association (1999) and the Heart Rhythm Society (2010).

Abstract

“Healthy” aging drives structural and functional changes in the heart including maladaptive electrical remodeling, fibrosis and inflammation, which lower the threshold for cardiovascular diseases such as heart failure (HF) and atrial fibrillation (AF). Relaxin’s short lifespan (2_3h) but long-lasting protective actions suggested that relaxin acts at a genomic level to reverse maladaptive remodeling in AF, HF and aging. Here we show that a 2-week treatment with Relaxin (RLX) (0.4 mg/kg/day) of aged (24months old F-344 rats) increases the expression of voltage-gated Na+ channels (mRNA, Nav1.5 and INa), connexin-43, abrogates inflammatory and immune responses and reverses myocardial fibrosis and cellular hypertrophy of the aged hearts. RLX acts directly at a wide range of cell types in the cardiovascular system that express its cognate GPCR receptor, RXFP1. RNA-seq analysis of young and aged hearts with and without RLX-treatment revealed that “normal” aging altered the expression of ~10% of genes expressed in the ventricles, including ion channels, components of fibrosis, hemodynamic biomarkers, immune and inflammatory responses which were reversed by Relaxin. Isolated rat cardiac myocytes were incubated in RLX (25-50 nM) for 48 hours and analyzed compared to control myocytes which revealed a RLX dependent increase in Nav1.5, Wnt1, ?-catenin and connexin 43 at intercalated disks. Cardiac fibroblasts were not significantly altered by RLX but fibroblasts activated with TGF?1 The extensive cardiovascular remodeling caused by Relaxin is mediated through the activation of the Wnt/?-catenin signaling pathway which was otherwise suppressed by in adult cardiomyocytes intracellular by cytosolic Dickkopf1 (Dkk1). Wnt/?-catenin signaling is a mechanism that can explain the pleiotropic actions of Relaxin and the marked reversal of genomic changes that occur in aged hearts.