Int J Biol Sci 2021; 17(10):2399-2416. doi:10.7150/ijbs.56379

Research Paper

Soluble Receptor for Advanced Glycation End-products regulates age-associated Cardiac Fibrosis

Francesco Scavello1*, Filippo Zeni1*, Giuseppina Milano2#, Federica Macrì1, Stefania Castiglione1, Estella Zuccolo1, Alessandro Scopece2, Giovanni Pezone1, Calogero C. Tedesco3, Patrizia Nigro2, Genny Degani4, Elisa Gambini2, Fabrizio Veglia3, Laura Popolo4, Giulio Pompilio2, Gualtiero I. Colombo5, Marco E. Bianchi6, Angela Raucci1✉

1. Unit of Experimental Cardio-Oncology and Cardiovascular Aging, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
2. Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
3. Unit of Biostatistics, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
4. Department of Biosciences, University of Milan, Milan, Italy.
5. Unit of Immunology and Functional Genomics, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
6. Chromatin Dynamics Unit, San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy.
*These authors contributed equally to this work.
#Department of Cœur-Vaisseaux, Laboratory of Cardiovascular Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Scavello F, Zeni F, Milano G, Macrì F, Castiglione S, Zuccolo E, Scopece A, Pezone G, Tedesco CC, Nigro P, Degani G, Gambini E, Veglia F, Popolo L, Pompilio G, Colombo GI, Bianchi ME, Raucci A. Soluble Receptor for Advanced Glycation End-products regulates age-associated Cardiac Fibrosis. Int J Biol Sci 2021; 17(10):2399-2416. doi:10.7150/ijbs.56379. Available from https://www.ijbs.com/v17p2399.htm

File import instruction

Abstract

Myocardial aging increases the cardiovascular risk in the elderly. The Receptor for Advanced Glycation End-products (RAGE) is involved in age-related disorders. The soluble isoform (sRAGE) acts as a scavenger blocking the membrane-bound receptor activation. This study aims at investigating RAGE contribution to age-related cardiac remodeling.

We analyzed the cardiac function of three different age groups of female Rage-/- and C57BL/6N (WT) mice: 2.5- (Young), 12- (Middle-age, MA) and 21-months (Old) old. While aging, Rage-/- mice displayed an increase in left ventricle (LV) dimensions compared to age-matched WT animals, with the main differences observed in the MA groups. Rage-/- mice showed higher fibrosis and a larger number of α-Smooth Muscle Actin (SMA)+ cells with age, along with increased expression of pro-fibrotic Transforming Growth Factor (TGF)-β1 pathway components. RAGE isoforms were undetectable in LV of WT mice, nevertheless, circulating sRAGE declined with aging and inversely associated with LV diastolic dimensions. Human cardiac fibroblasts stimulated with sRAGE exhibited a reduction in proliferation, pro-fibrotic proteins and TGF-beta Receptor 1 (TGFbR1) expression and Smad2-3 activation. Finally, sRAGE administration to MA WT animals reduced cardiac fibrosis.

Hence, our work shows that RAGE associates with age-dependent myocardial changes and indicates sRAGE as an inhibitor of cardiac fibroblasts differentiation and age-dependent cardiac fibrosis.

Keywords: sRAGE, aging, fibrosis, heart failure, cardiac remodeling