Col1a2-Deleted Mice Have Defective Type I Collagen and Secondary Reactive Cardiac Fibrosis with Altered Hypertrophic Dynamics.

Abstract

RATIONALE:

The adult cardiac extracellular matrix (ECM) is largely comprised of type I collagen. In addition to serving as the primary structural support component of the cardiac ECM, type I collagen also provides an organizational platform for other ECM proteins, matricellular proteins, and signaling components that impact cellular stress sensing in vivo.

OBJECTIVE:

Here we investigated how the content and integrity of type I collagen affect cardiac structure function and response to injury.

METHODS AND RESULTS:

We generated and characterized Col1a2-/- mice using standard gene targeting. Col1a2-/- mice were viable, although by young adulthood their hearts showed alterations in ECM mechanical properties, as well as an unanticipated activation of cardiac fibroblasts and induction of a progressive fibrotic response. This included augmented TGFβ activity, increases in fibroblast number, and progressive cardiac hypertrophy, with reduced functional performance by 9 months of age. Col1a2-loxP-targeted mice were also generated and crossed with the tamoxifen-inducible Postn-MerCreMer mice to delete the Col1a2 gene in myofibroblasts with pressure overload injury. Interestingly, while germline Col1a2-/- mice showed gradual pathologic hypertrophy and fibrosis with aging, the acute deletion of Col1a2 from activated adult myofibroblasts showed a loss of total collagen deposition with acute cardiac injury and an acute reduction in pressure overload-induce cardiac hypertrophy. However, this reduction in hypertrophy due to myofibroblast-specific Col1a2 deletion was lost after 2 and 6 weeks of pressure overload, as fibrotic deposition accumulated.

CONCLUSIONS:

Defective type I collagen in the heart alters the structural integrity of the ECM and leads to cardiomyopathy in adulthood, with fibroblast expansion, activation, and alternate fibrotic ECM deposition. However, acute inhibition of type I collagen production can have an anti-fibrotic and anti-hypertrophic effect.

• Authors: Stephanie L K Bowers, Qinghang Meng, Yasuhide Kuwabara, Jiuzhou Huo, Rachel Minerath, Allen J York, Michelle A Sargent, Vikram Prasad, Anthony J Saviola, David Ceja Galindo, Kirk C Hansen, Ronald J Vagnozzi, Katherine E Yutzey, Jeffery D Molkentin
• Journal: Cells (Cells) Vol. 12 Issue 17 (08 30 2023) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 37681905 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• Collagen Type I, alpha2 Subunit
• Col1a2 protein, mouse

Topics

• Animals
• Mice
• Cardiomegaly (genetics)
• Cardiomyopathies
• Collagen Type I (genetics)
• Fibrosis