Abstract 540: Mineralocorticoid Receptor Antagonism Prevents The Aortic Dilatation And Extracellular Matrix Degradation Induced By Beta-adrenoceptor Overactivation
Chronic stimulation of β-adrenoceptor (β-AR) and activation of renin-angiotensin-aldosterone system are common feature of cardiovascular diseases as heart failure and hypertension. β-AR overactivation induces cardiac remodeling, which contribute to cardiac dysfunction. However, it is unknown whether it alters arterial structure. Here, we demonstrated that β-AR overactivation induced by isoproterenol (ISO) treatment in Wistar rats (0.3 mg/kg/day, for 7 days) compared to control group (vs. CT, *p<0.05) increased thoracic aortic lumen area (CT: 1.8±0.06 vs. ISO: 2.3±0.08* mm2) and internal diameter (ID) (CT: 1.63±0.28 vs. ISO: 1.77±0.08* mm), without changes on wall thickness (wt). ISO caused disorganization and rupture of elastin fibers (Score; CT: 1.53±0.07 vs. ISO: 2.52±0.27*) and reduced aortic collagen deposition measured by picrosiuris red (CT: 56±3 vs. ISO: 32±2* A.U./vessel area). These alterations induced by ISO were associated with increased phosphorylation of extracellular signal-regulated kinase 1/2 (p-ERK/ ERK; CT: 0.75±0.07 vs. ISO: 0.95±0.05* A.U.); increased matrix metalloproteinase (MMP)-2 activity evaluated by zymography (CT: 4.0±0.9 vs. ISO: 10.8±1.2* A.U.); and reduced protein expression of TIMP-2 (CT: 0.95 ±0.07 vs. ISO: 0.48±0.08* A.U.) and collagen I/III (CT: 0.9±0.08 vs. ISO: 0.6±0.06* A.U.). ISO treatment did not change mean arterial pressure (MAP); however, it increased the mechanical forces circumferential wall tension (CWT= MAPxID/2; CT: 10.1±0.35 vs. ISO: 11.6±0.35* 103dyn/cm) and tensile stress (TS=CWT/wt; CT: 102±6 vs. ISO: 121±6* 104dyn/cm2) on aorta. The co-treatment with spironolactone (SPI, 200 mg/kg/day), a mineralocorticoid receptor (MR) antagonist prevented the ISO-induced aortic structural changes, MMP-2 and ERK1/2 activation, as well as the reductions on collagen and TIMP-2 expression. However, SPI did not modify MAP, CWS or TS. The results suggest that β-AR overactivation induces an aneurysm-like thoracic aortic remodeling characterized by vessel dilatation and extracellular matrix degradation, associated with MMP-2 and ERK1/2 activation. This remodeling and signaling were prevented by MR antagonist, independently of changes on aortic wall tension and tensile stress.
Author Disclosures: S.P. Clerici: None. J.A. Victorio: None. J.C. Santos-Silva: None. K.L. Bessa: None. D.L. Ferrucci: None. H.F. Carvalho: None. L.V. Rossoni: None. A.P. Davel: None.
- © 2014 by American Heart Association, Inc.