Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac performance

Rebecca S. Keller, Shaw Yung Shai, Christopher J. Babbitt, Can G. Pham, R. John Solaro, Maria L. Valencik, Joseph C. Loftus, Robert S. Ross

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

The molecular mechanisms that regulate the cardiac hypertrophic response and the progression from compensated hypertrophy to decompensated heart failure have not been thoroughly defined. Alteration in cardiac extracellular matrix is a distinguishing characteristic of these pathological processes. Integrins, cell surface receptors that mediate cellular adhesion to the extracellular matrix, are signaling molecules that possess mechanotransduction properties. Therefore, we hypothesized that integrins are likely candidates to play an important role in cardiac function. To test this hypothesis, transgenic mice were constructed in which normal integrin function was disrupted by expression of a chimeric molecule encoding the transmembrane and extracellular domains of the Tac subunit of the IL-2 receptor, fused to the cytoplasmic domain of β1A integrin (Tacβ1A). Using the myosin heavy chain promoter to target expression of this chimera to the cardiac myocyte, transgenic mice were generated that had varied levels of transgene expression. Multiple transgenic founders that expressed the transgene at high levels, died perinatally and exhibited replacement fibrosis. Lines that survived showed 1) hypertrophic changes concordant with reduction in endogenous β1 integrin levels, or 2) reduced basal contractility and relaxation as well as alterations in components of integrin signaling pathways. These data support an important role for β1 integrin in normal cardiac function.

Original languageEnglish (US)
Pages (from-to)1079-1090
Number of pages12
JournalAmerican Journal of Pathology
Volume158
Issue number3
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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