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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Perrino, C; Naga Prasad, SV; Mao, L; Noma, T; Yan, Z; Kim, H-S; Smithies, O; Rockman, HA

Published Date

  • June 2006

Published In

Volume / Issue

  • 116 / 6

Start / End Page

  • 1547 - 1560

PubMed ID

  • 16741575

Pubmed Central ID

  • 16741575

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI25397

Language

  • eng