Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension

Circ Res. 2005 Sep 16;97(6):596-604. doi: 10.1161/01.RES.0000182425.49768.8a. Epub 2005 Aug 18.

Abstract

Transgenic mice overexpressing the calcium binding protein, S100A4/Mts1, occasionally develop severe pulmonary vascular obstructive disease. To understand what underlies this propensity, we compared the pulmonary vascular hemodynamic and structural features of S100A4/Mts1 with control C57Bl/6 mice at baseline, following a 2-week exposure to chronic hypoxia, and after 1 and 3 months "recovery" in room air. S100A4/Mts1 mice had greater right ventricular systolic pressure and right ventricular hypertrophy at baseline, which increased further with chronic hypoxia and was sustained after 3 months "recovery" in room air. These findings correlated with a heightened response to acute hypoxia and failure to vasodilate with nitric oxide or oxygen. S100A4/Mts1 mice, when compared with C57Bl/6 mice, also had impaired cardiac function judged by reduced ventricular elastance and decreased cardiac output. Despite higher right ventricular systolic pressures with chronic hypoxia, S100A4/Mts1 mice did not develop more severe PVD, but in contrast to C57Bl/6 mice, these features did not regress on return to room air. Microarray analysis of lung tissue identified a number of genes differentially upregulated in S100A4/Mts1 versus control mice. One of these, fibulin-5, is a matrix component necessary for normal elastin fiber assembly. Fibulin-5 was localized to pulmonary arteries and associated with thickened elastic laminae. This feature could underlie attenuation of pulmonary vascular changes in response to elevated pressure, as well as impaired reversibility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Elastin / genetics*
  • Extracellular Matrix Proteins / genetics*
  • Female
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism*
  • Hypoxia / complications
  • Lung / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Elastase / metabolism
  • RNA, Messenger / analysis
  • Recombinant Proteins / genetics*
  • S100 Calcium-Binding Protein A4
  • S100 Proteins / physiology*
  • Systole

Substances

  • Extracellular Matrix Proteins
  • Fbln5 protein, mouse
  • RNA, Messenger
  • Recombinant Proteins
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • Elastin
  • Pancreatic Elastase