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 Ϫ/Ϫ and FXIII Ϫ/ϩ (FXIII activity Ͻ5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII Ϫ/Ϫ 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 Ϫ/Ϫ mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII Ϫ/Ϫ mice receiving supplemental FXIII than in FXIII Ϫ/Ϫ mice (PϽ0.05). In FXIII Ϫ/Ϫ but not in reconstituted FXIII Ϫ/Ϫ mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase-polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII Ϫ/Ϫ mice was independent of intercellular adhesion molecule and lipopolysaccharideinduced 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 Ϫ/Ϫ mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII Ϫ/Ϫ mice. Conclusions-These data suggest that FXIII has an important role in murine myocardial healing after infarction.

Roles of transglutaminases in cardiac and vascular diseases

“…Cardiac rupture of factor XIII deficient mice (FXIII −/− and FXIII −/+ ) occurred between 3 and 5 days after MI, consistent with clinical observations of this complication (180). Cardiac ruptures were likely due to an imbalance in ECM turnover, since MMP-9 expression was 7-fold higher and collagen-1 production was 53% lower in FXIII −/− mice (180). Replenishing Factor XIII levels in FXIII −/− mice reduced cardiac rupture and death rates to those observed in wild type mice.…”

“…Mice with even relatively mild deficiency of factor XIII (70% activity in FXIII+/− mice) displayed this phenotype. Cardiac rupture of factor XIII deficient mice (FXIII −/− and FXIII −/+ ) occurred between 3 and 5 days after MI, consistent with clinical observations of this complication (180). Cardiac ruptures were likely due to an imbalance in ECM turnover, since MMP-9 expression was 7-fold higher and collagen-1 production was 53% lower in FXIII −/− mice (180).…”

“…Factor XIII deficient mice have a normal cardiac phenotype, but exhibit impaired healing and fatal rupture of the LV after myocardial infarction (180). Mice with even relatively mild deficiency of factor XIII (70% activity in FXIII+/− mice) displayed this phenotype.…”

“…FXIII administration also reduced MMP-9 expression but failed to improve collagen-1 production. The authors speculated that the lack of increased collagen syntheses with intravenous supplemental FXIII could be due to failure of this therapy to replenish intracellular factor XIII in platelets and monocytes/macrophages (180).…”

Relaxin remodels fibrotic healing following myocardial infarction

“…Earlier studies showed deleterious consequences (including a worsening of ventricular remodeling) following inhibition of fibrotic healing or the inflammatory response after infarction by means of corticosteroids. 29,30 Recent research on genetically modified mice has also demonstrated the adverse consequences of impaired fibrotic healing after MI leading to aggravated ventricular rupture and remodeling, 31,32 although the suppression of excessive matrix deposition is believed to be beneficial in the context of stem cell based therapies. Our findings showed that fibrotic healing post-infarction can be therapeutically remodeled by relaxin leading to a reduced density of fibrotic tissue across infarcted, non-infarcted, and border zones.…”