Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction.

Abstract

BACKGROUND:

Identification of key molecular players in myocardial healing could lead to improved therapies, reduction of scar formation, and heart failure after myocardial infarction (MI). We hypothesized that clotting factor XIII (FXIII), a transglutaminase involved in wound healing, may play an important role in MI given prior clinical and mouse model data.

METHODS AND RESULTS:

To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we prospectively studied myocardial repair in FXIII-deficient mice. All FXIII(-/-) and FXIII(-)(/+) (FXIII activity <5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII(-/-) mice that received 5 days of intravenous FXIII replacement therapy had normal survival rates; however, cardiac MRI demonstrated worse left ventricular remodeling in these reconstituted FXIII(-/-) mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII(-/-) mice receiving supplemental FXIII than in FXIII(-/-) mice (P<0.05). In FXIII(-/-) but not in reconstituted FXIII(-/-) mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase-polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII(-/-) mice was independent of intercellular adhesion molecule and lipopolysaccharide-induced CXC chemokine, both important for cell migration. After MI, expression of matrix metalloproteinase-9 was 650% higher and collagen-1 was 53% lower in FXIII(-/-) mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII(-/-) mice.

CONCLUSIONS:

These data suggest that FXIII has an important role in murine myocardial healing after infarction.

• Authors: Matthias Nahrendorf, Kai Hu, Stefan Frantz, Farouc A Jaffer, Ching-Hsuan Tung, Karl-Heinz Hiller, Sabine Voll, Peter Nordbeck, David Sosnovik, Stefan Gattenlöhner, Mikhail Novikov, Gerhard Dickneite, Guy L Reed, Peter Jakob, Anthony Rosenzweig, Wolfgang R Bauer, Ralph Weissleder, Georg Ertl
• Journal: Circulation (Circulation) Vol. 113 Issue 9 Pg. 1196-202 (Mar 07 2006) ISSN: 1524-4539 [Electronic] United States
• PMID: 16505171 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Extracellular Matrix Proteins
• Factor XIII

Topics

• Animals
• Chemotaxis, Leukocyte
• Extracellular Matrix Proteins (analysis, genetics)
• Factor XIII (physiology)
• Factor XIII Deficiency (complications)
• Heart Rupture, Post-Infarction (etiology)
• Mice
• Mice, Knockout
• Myocardial Infarction (complications)
• Neutrophils (physiology)
• Ventricular Remodeling
• Wound Healing