Cardiomyocyte-fibroblast signaling in atrial fibrillation

/ ABSTRACT Atrial fibrillation (AF) contributes to at least 175,000 deaths per year in the US alone, and is a leading cause of stroke. AF is expected to affect twelve million people in the U.S. by 2030. Atrial fibrosis is a key disease feature linked to increased morbidity and mortality in patients with AF. Fibrosis (especially interstitial) creates a substrate for atrial re-entrant arrhythmias and is associated with therapy resistance. Dysfunction of atrial cardiofibroblasts (ACFs) that secrete excessive collagen into the extracellular matrix (ECM) is one of the important mechanisms leading to fibrosis. Our recent studies revealed that calcitonin (CT), a paracrine signaling molecule released by atrial cardiomyocytes (ACMs), suppresses collagen and other profibrotic ECM proteins production by ACFs. The long-term goal of this project is to dissect the molecular and cellular basis of the CT signaling pathway in relation to atrial fibrogenesis in AF in order to uncover new targets for future therapies in AF. The central project hypothesis is that reduced CT production by ACMs, miR-31-dependent downregulation of CT-receptor (CTR) expression, and activated BMP1 signaling downstream of the CTR promote atrial remodeling, fibrogenesis and AF progression. Two Specific Aims will be pursued: Aim 1) Determine whether miR-31-5p, via reduced CTR expression, drives atrial profibrotic remodeling and AF development, and Aim 2) Define the role of BMP1 and MGP in the CT/CTR signaling pathway in AF. This project is supported by a large amount of preliminary data that support the central hypothesis. The proposed studies will be performed in freshly isolated and cultured ACFs obtained from the right and left atria of patients with persistent AF (vs controls in sinus rhythm, or, in some cases, with paroxysmal AF), and from various genetic mouse models of spontaneous AF. Numerous new reagents and innovative multi-disciplinary approaches will be used to dissect the molecular basis of ACF phenotype changes and profibrotic remodeling driven by changes in the CT-CTR-BMP1 signaling axis. Impact: These studies are expected to underpin how suppressed CT/CTR signaling contributes to atrial fibrosis and arrhythmia development, and to serve as a platform for the validation of novel treatment modalities (up- and down-stream of CT/CTR axis) aimed at preventing atrial fibrogenesis and ameliorating AF development. Project Number: 3R01HL174510-01A1S1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Xander Wehrens | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $72,980 | Activity Code: R01 | Study Section: Integrative Myocardial Physiology/Pathophysiology B Study Section[MPPB] View on NIH RePORTER: https://reporter.nih.gov/project-details/3R01HL17451001A1S1