Sympathoadrenergic suppression improves heart function by upregulating the ratio of sRAGE/RAGE in hypertension with metabolic syndrome. (September 2018)

• Record Type: Journal Article
• Authors: Selejan, Simina-Ramona; Linz, Dominik; Tatu, Anna-Maria; Hohl, Mathias; Speer, Thimoteus; Ewen, Sebastian; Mahfoud, Felix; Kindermann, Ingrid; Zamyatkin, Olesja; Kazakov, Andrey; Laufs, Ulrich; Böhm, Michael
• Is Part Of: Journal of molecular and cellular cardiology. Volume 122(2018)
• Page Start: 34
• Page End: 46
• Publication Date: 2018-09
• Subjects: Receptor for advanced glycation end products -- hypertension -- metabolic syndrome -- renal denervation -- fibrosis -- HMGB1 protein; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.08.003
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Receptors-for-Advanced-Glycation-End-products (RAGE) activate pro-inflammatory programs mediated by carboxymethyllysine (CML) and high-mobility-group-box1 protein (HMGB1). The soluble isoform sRAGE neutralizes RAGE-ligands preventing cardiovascular complications in conditions associated with increased sympathetic activation like hypertension and diabetes. The effects of sympathetic modulation on RAGE/sRAGE-balance and end-organ damage in metabolic syndrome on top of hypertension remains unknown. We hypothesized that increased sympathoadrenergic activity might lead to an unfavourable RAGE/sRAGE regulation. Renal denervation (RDN) was used to modulate sympathetic activation in obese spontaneously hypertensive rats (SHRobRDN) versus sham-operated obese spontaneously hypertensive rats (SHRob), their hypertensive lean controls (SHR) and non-hypertensive controls. Cardiac fibrosis was assessed by histological analysis and sRAGE/RAGE and ligand levels by Western blotting. Levels of CML and HMGB1 were highest in SHRob and were significantly lowered by RDN in serum (−44% and −45%) and myocardium (−25% and −52%). Myocardial RAGE was increased in SHR (+72% versus controls) and in SHRob (+68% versus SHR) while sRAGE decreased (−50% in SHR versus controls and −51% in SHRob versus SHR). RDN reduced myocardial RAGE expression. (−20%) and increased sRAGE levels in heart (+80%) and serum (+180%) versus sham-operated SHRob. Myocardial fibrosis correlated inversely with myocardial sRAGE content (r = −0.79; p = .004; n = 10). Myocardial sRAGE shedding active A-Disintegrin-And-Metalloprotease-10 (ADAM-10) was decreased in SHR (−33% versus controls) and in SHRob (−54% versus SHR), and was restored after RDN (+129% versus SHRob). Serum ADAM-10 activity was also decreased in SHRob (−66% versus SHR) and restored after RDN (+150% versus SHRob). In vitro, isoproterenol induced a ß1-adrenergic receptor mediated increase of RAGE expression in splenocytes (+200%) and decreased sRAGE secretion of splenocytes and cardiac fibroblasts (−50% and −49%) by ß2-adrenergic receptor stimulation mediated suppression of ADAM-10 activity. In conclusion, sympathetic activity affects sRAGE/RAGE-balance, which can be suppressed through sympathetic modulation by RDN, preventing RAGE-induced cardiac damage in hypertension with metabolic syndrome. Highlights: Sympathetic activity regulates the RAGE/sRAGE-ratio in the heart. Sympathetic modulation by renal denervation decreases myocardial RAGE/sRAGE-ratio. RAGE cleaving active ADAM-10 is modulated by renal denervation. Renal denervation decreases myocardial fibrosis in rats with metabolic syndrome. Renal denervation decreases blood and myocardial levels of RAGE-ligands.