Elevated mineralocorticoid receptor activity in aged rat vascular smooth muscle cells promotes a proinflammatory phenotype via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and epidermal growth factor receptor-dependent pathways

Hypertension. 2010 Jun;55(6):1476-83. doi: 10.1161/HYPERTENSIONAHA.109.148783. Epub 2010 Apr 26.

Abstract

Arterial aging is a predominant risk factor for the onset of cardiovascular diseases, such as hypertension, myocardial infarction, or stroke. Aging is associated with intravascular renin-angiotensin system activation, increased vascular stiffness, intima-media thickening, and a proinflammatory phenotype. Little is known about the influence of aldosterone on arterial aging. Hence, we hypothesized that aldosterone and mineralocorticoid receptor (MR) activation might contribute to and possibly accelerate the arterial aging process. We demonstrate increased MR expression in whole aortae and early passage aortic vascular smooth muscle cells from aged (30 months) compared with adult (8 months) F344XBN rats. Sensitivity to aldosterone-induced extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activity is increased in aged cells. MR blockade and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase inhibition prevent age-associated increases of transforming growth factor-beta, intercellular adhesion molecule 1, and procollagen 1. Aldosterone increases expression of proinflammatory marker proteins, shifting the phenotype of adult vascular smooth muscle cells toward the proinflammatory phenotype of aged rats. Epidermal growth factor receptor expression is increased with age and by aldosterone, and inhibition of epidermal growth factor receptor tyrosine kinase decreases age-associated proinflammatory marker expression. Our data support the hypothesis that increased constitutive MR signaling may promote and amplify age-associated inflammation that accompanies arterial aging through increased angiotensin II-stimulated expression of MR and enhanced sensitivity to aldosterone-mediated extracellular signal-regulated kinase 1/2 activation, likely related to increased epidermal growth factor receptor expression.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Analysis of Variance
  • Animals
  • Aorta, Thoracic / cytology
  • Blotting, Western
  • Cells, Cultured
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Immunohistochemistry
  • Inflammation Mediators / metabolism
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Models, Animal
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / physiology*
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / physiology
  • Phenotype
  • Probability
  • Random Allocation
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred F344
  • Receptors, Mineralocorticoid / genetics
  • Receptors, Mineralocorticoid / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction

Substances

  • Inflammation Mediators
  • Receptors, Mineralocorticoid
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3