Soluble Interleukin-6 Receptor Regulates Interleukin-6-Dependent Vascular Remodeling in Long-Distance Runners.

Paulina Villar-Fincheira,Felipe Contreras-Briceño,Nicole Cancino-Arenas,Lorena García,Mario Chiong,Rodrigo Troncoso,Fernanda Sanhueza-Olivares,Nicole Bruneau,Ignacio Norambuena-Soto,Luigi Gabrielli,Jorge Mandiola,Tomás Hernández-Díaz,María Paz Ocaranza,Aaron J Paredes

doi:10.3389/fphys.2021.722528

Abstract

Little is known about the effects of training load on exercise-induced plasma increase of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) and their relationship with vascular remodeling. We sought to evaluate the role of sIL 6R as a regulator of IL-6-induced vascular remodeling. Forty-four male marathon runners were recruited and allocated into two groups: low-training (LT, <100 km/week) and high-training (HT, ≥100 km/week), 22 athletes per group. Twenty-one sedentary participants were used as reference. IL-6, sIL-6R and sgp130 levels were measured in plasma samples obtained before and immediately after finishing a marathon (42.2-km). Aortic diameter was measured by echocardiography. The inhibitory effect of sIL-6R on IL-6-induced VSMC migration was assessed using cultured A7r5 VSMCs. Basal plasma IL-6 and sIL-6R levels were similar among sedentary and athlete groups. Plasma IL-6 and sIL-6R levels were elevated after the marathon, and HT athletes had higher post-race plasma sIL-6R, but not IL-6, level than LT athletes. No changes in sgp130 plasma levels were found in LT and HT groups before and after running the marathon. Athletes had a more dilated ascending aorta and aortic root than sedentary participants with no differences between HT and LT athletes. However, a positive correlation between ascending aorta diameter and plasma IL-6 levels corrected by training load and years of training was observed. IL-6 could be responsible for aorta dilation because IL-6 stimulated VSMC migration in vitro, an effect that is inhibited by sIL-6R. However, IL-6 did not modify cell proliferation, collagen type I and contractile protein of VSMC. Our results suggest that exercise induces vascular remodeling. A possible association with IL-6 is proposed. Because sIL-6R inhibits IL-6-induced VSMC migration, a possible mechanism to regulate IL-6-dependent VSMC migration is also proposed.

Highlights

MATERIALS AND METHODSModerate exercise is considered an essential element of maintaining cardiovascular health (Morris et al, 1953)
Because IL-6 binds to soluble form of IL-6 receptor (IL-6R) (sIL-6R), we evaluated the proportion of IL-6 that was complexed by sIL-6R at baseline and after the marathon
Because an increase in sIL-6R levels was observed in the athletes, we evaluated the effects of sIL-6R on VSMC migration. sIL-6R did not alter A7r5 VSMC migration levels (Figures 5A,B)

Summary

Introduction

MATERIALS AND METHODSModerate exercise is considered an essential element of maintaining cardiovascular health (Morris et al, 1953). Training can stimulate the formation of new capillaries by angiogenesis and increase the size of the conduit artery by arteriogenesis (Green and Smith, 2018). This physiological vascular remodeling, known as “athlete’s artery,” increases blood flow to skeletal muscles and other organs to fulfill the nutrient and oxygen requirements of athletes (Green and Smith, 2018). Plasma IL-6 levels increases in response to a variety of acute exercise types (Catoire and Kersten, 2015). Because IL-6 stimulates VSMC proliferation and migration (Morimoto et al, 1991; Wang and Newman, 2003), reduces VSMC contractility (Ohkawa et al, 1994) and induces production of matrix metalloproteinases (MMP)-9 and MMP-1 (Zhu et al, 2000), it has been proposed that IL-6 could be responsible for exercise-induced vascular remodeling

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