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Published on: November 22, 2013
Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac
R S Keller1, S Y Shai, C J Babbitt
1Department of Physiology, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90095-1751, USA.
Insights
Beta-1 integrin plays a crucial role in cardiac function. Disrupting its function in transgenic mice led to cardiac hypertrophy and impaired contractility, highlighting its importance in heart health.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Integrin Signaling
Background:
- Cardiac hypertrophy can progress to heart failure, with extracellular matrix alterations being a key feature.
- Integrins are cell surface receptors involved in cell adhesion and mechanotransduction, suggesting a role in cardiac regulation.
Purpose of the Study:
- To investigate the role of beta-1 integrin in cardiac function.
- To determine if integrin dysfunction contributes to pathological cardiac remodeling.
Main Methods:
- Generated transgenic mice expressing a chimeric molecule (Tacbeta(1A)) to disrupt normal beta-1 integrin function in cardiac myocytes.
- Utilized the alpha myosin heavy chain promoter for targeted cardiac-specific expression.
- Analyzed cardiac phenotype, transgene expression levels, and endogenous beta-1 integrin levels.
Main Results:
- High-level transgene expression resulted in perinatal lethality and replacement fibrosis.
- Surviving lines exhibited hypertrophic changes correlated with reduced endogenous beta-1 integrin.
- Other lines showed decreased contractility, impaired relaxation, and altered integrin signaling pathways.
Conclusions:
- Beta-1 integrin is essential for normal cardiac function.
- Disruption of beta-1 integrin signaling contributes to cardiac hypertrophy and dysfunction.
- Integrin-mediated mechanotransduction is critical for maintaining cardiac homeostasis.
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 beta(1A) integrin (Tacbeta(1A)). Using the alpha 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 beta(1) 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 beta(1) integrin in normal cardiac function.
