Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension

Matthew S. Lemler, Roger D. Bies, Maria G. Frid, Amornrate Sastravaha, Lawrence S. Zisman, Teresa Bohlmeyer, A. Martin Gerdes, John T. Reeves, Kurt R. Stenmark

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Abstract

Previous studies have demonstrated that environmentally or genetically induced changes in the intracellular proteins that compose the cytoskeleton can contribute to heart failure. Because neonatal right ventricular myocytes are immature and are in the process of significant cytoskeletal change, we hypothesized that they may be particularly susceptible to pressure stress. Newborn calves exposed to hypobaric hypoxia (barometric pressure = 430 mmHg) for 14 days developed severe pulmonary hypertension (pulmonary arterial pressure = 101 ± 6 vs. 27 ± 1 mmHg) and right heart failure compared with age-matched controls. Light microscopy showed partial loss of myocardial striations in the failing neonatal right but not left ventricles and in neither ventricle of adolescent cattle dying of altitude-induced right heart failure. In neonatal calves, immunohistochemical analysis of the cytoskeletal proteins (vinculin, metavinculin, desmin, vimentin, and cadherin) showed selectively, within the failing right ventricles, patchy areas characterized by loss and disorganization of costameres and intercalated discs. Within myocytes from the failing ventricles, vinculin and desmin were observed to redistribute diffusely within the cytosol, metavinculin appeared in disorganized clumps, and vimentin immunoreactivity was markedly decreased. Western blot analysis of the failing right ventricular myocardium showed, compared with control, vinculin and desmin to be little changed in total content but redistributed from insoluble (structural) to soluble (cytosolic) fractions; metavinculin total content was markedly decreased, tubulin content increased, particularly in the structural fraction, and cadherin total content and distribution were unchanged. We conclude that hypoxic pulmonary hypertensive-induced neonatal right ventricular failure is associated with disorganization of the cytoskeletal architecture.

Original languageEnglish (US)
Pages (from-to)H1365-H1376
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume279
Issue number3 48-3
StatePublished - Oct 4 2000

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Keywords

  • Cadherin
  • Cor pulmonale
  • Costameres
  • Cytoskeleton
  • Desmin
  • Intercalated disks
  • Metavinculin
  • Tubulin
  • Vinculin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Lemler, M. S., Bies, R. D., Frid, M. G., Sastravaha, A., Zisman, L. S., Bohlmeyer, T., Gerdes, A. M., Reeves, J. T., & Stenmark, K. R. (2000). Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension. American Journal of Physiology - Heart and Circulatory Physiology, 279(3 48-3), H1365-H1376.