Renal denervation reduces atrial remodeling in hypertensive rats with metabolic syndrome.

Abstract

Atrial fibrillation (AF) is highly prevalent in hypertensive patients with metabolic syndrome and is related to inflammation and activation of the sympathoadrenergic system. The multi-ligand Receptor-for-Advanced-Glycation-End-products (RAGE) activates inflammation-associated tissue remodeling and is regulated by the sympathetic nervous system. Its counterpart, soluble RAGE (sRAGE), serves as anti-inflammatory decoy receptor with protective properties. We investigated the effect of sympathetic modulation by renal denervation (RDN) on atrial remodeling, RAGE/sRAGE and RAGE ligands in metabolic syndrome. RDN was performed in spontaneously hypertensive obese rats (SHRob) with metabolic syndrome compared with lean spontaneously hypertensive rats (SHR) and with normotensive non-obese control rats. Blood pressure and heart rate were measured by telemetry. The animals were killed 12 weeks after RDN. Left atrial (LA) and right atrial (RA) remodeling was assessed by histological analysis and collagen types. Sympathetic innervation was measured by tyrosine hydroxylase staining of atrial nerve fibers, RAGE/sRAGE, RAGE ligands, cytokine expressions and inflammatory infiltrates were analyzed by Western blot and immunofluorescence staining. LA sympathetic nerve fiber density was higher in SHRob (+44%) versus controls and reduced after RDN (-64% versus SHRob). RAGE was increased (+718%) and sRAGE decreased (- 62%) in SHRob as compared with controls. RDN reduced RAGE expression (- 61% versus SHRob), significantly increased sRAGE levels (+162%) and induced a significant decrease in RAGE ligand levels in SHRob (- 57% CML and - 51% HMGB1) with reduced pro-inflammatory NFkB activation (- 96%), IL-6 production (- 55%) and reduced inflammatory infiltrates. This led to a reduction in atrial fibrosis (- 33%), collagen type I content (- 72%), accompanied by reduced LA myocyte hypertrophy (- 21%). Transfection experiments on H9C2 cardiomyoblasts demonstrated that RAGE is directly involved in fibrosis formation by influencing cellular production of collagen type I. In conclusion, suppression of renal sympathetic nerve activity by RDN prevents atrial remodeling in metabolic syndrome by reducing atrial sympathetic innervation and by modulating RAGE/sRAGE balance and reducing pro-inflammatory and pro-fibrotic RAGE ligands, which provides a potential therapeutic mechanism to reduce the development of AF.

• Authors: Simina-Ramona Selejan, Dominik Linz, Muriel Mauz, Mathias Hohl, Anh Khoa Dennis Huynh, Thimoteus Speer, Jan Wintrich, Andrey Kazakov, Christian Werner, Felix Mahfoud, Michael Böhm
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 117 Issue 1 Pg. 36 (07 14 2022) ISSN: 1435-1803 [Electronic] Germany
• PMID: 35834066 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Ager protein, rat
• Collagen Type I
• Ligands
• Receptor for Advanced Glycation End Products

Topics

• Animals
• Atrial Fibrillation (metabolism)
• Atrial Remodeling
• Collagen Type I
• Denervation (methods)
• Fibrosis
• Hypertension (complications, metabolism)
• Inflammation (metabolism)
• Kidney (innervation, surgery)
• Ligands
• Metabolic Syndrome (complications, metabolism, therapy)
• Obesity (metabolism)
• Rats
• Rats, Inbred SHR
• Receptor for Advanced Glycation End Products (metabolism)