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Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction.

Publication ,  Journal Article
Perrino, C; Naga Prasad, SV; Mao, L; Noma, T; Yan, Z; Kim, H-S; Smithies, O; Rockman, HA
Published in: J Clin Invest
June 2006

For over a century, there has been intense debate as to the reason why some cardiac stresses are pathological and others are physiological. One long-standing theory is that physiological overloads such as exercise are intermittent, while pathological overloads such as hypertension are chronic. In this study, we hypothesized that the nature of the stress on the heart, rather than its duration, is the key determinant of the maladaptive phenotype. To test this, we applied intermittent pressure overload on the hearts of mice and tested the roles of duration and nature of the stress on the development of cardiac failure. Despite a mild hypertrophic response, preserved systolic function, and a favorable fetal gene expression profile, hearts exposed to intermittent pressure overload displayed pathological features. Importantly, intermittent pressure overload caused diastolic dysfunction, altered beta-adrenergic receptor (betaAR) function, and vascular rarefaction before the development of cardiac hypertrophy, which were largely normalized by preventing the recruitment of PI3K by betaAR kinase 1 to ligand-activated receptors. Thus stress-induced activation of pathogenic signaling pathways, not the duration of stress or the hypertrophic growth per se, is the molecular trigger of cardiac dysfunction.

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

June 2006

Volume

116

Issue

6

Start / End Page

1547 / 1560

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Stress, Physiological
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Phenotype
  • Myocardium
  • Mice, Transgenic
  • Mice, Inbred C57BL
 

Citation

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Perrino, C., Naga Prasad, S. V., Mao, L., Noma, T., Yan, Z., Kim, H.-S., … Rockman, H. A. (2006). Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest, 116(6), 1547–1560. https://doi.org/10.1172/JCI25397
Perrino, Cinzia, Sathyamangla V. Naga Prasad, Lan Mao, Takahisa Noma, Zhen Yan, Hyung-Suk Kim, Oliver Smithies, and Howard A. Rockman. “Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction.J Clin Invest 116, no. 6 (June 2006): 1547–60. https://doi.org/10.1172/JCI25397.
Perrino C, Naga Prasad SV, Mao L, Noma T, Yan Z, Kim H-S, et al. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest. 2006 Jun;116(6):1547–60.
Perrino, Cinzia, et al. “Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction.J Clin Invest, vol. 116, no. 6, June 2006, pp. 1547–60. Pubmed, doi:10.1172/JCI25397.
Perrino C, Naga Prasad SV, Mao L, Noma T, Yan Z, Kim H-S, Smithies O, Rockman HA. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest. 2006 Jun;116(6):1547–1560.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

June 2006

Volume

116

Issue

6

Start / End Page

1547 / 1560

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Stress, Physiological
  • Signal Transduction
  • Receptors, Adrenergic, beta
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Phenotype
  • Myocardium
  • Mice, Transgenic
  • Mice, Inbred C57BL