Type I Collagen Cleavage Is Essential for Effective Fibrotic Repair after Myocardial Infarction

Abstract

Efficient deposition of type I collagen is fundamental to healing after myocardial infarction. Whether there is also a role for cleavage of type I collagen in infarct healing is unknown. To test this, we undertook coronary artery occlusion in mice with a targeted mutation (Col1a1 r/r ) that yields collagenase-resistant type I collagen. Eleven days after infarction, Col1a1 r/r mice had a lower mean arterial pressure and peak left ventricular systolic pressure, reduced ventricular systolic function, and worse diastolic function, compared with wild-type littermates. Infarcted Col1a1 r/r mice also had greater 30-day mortality, larger left ventricular lumens, and thinner infarct walls. Interestingly, the collagen fibril content within infarcts of mutant mice was not increased. However, circular polarization microscopy revealed impaired collagen fibril organization and mechanical testing indicated a predisposition to scar microdisruption. Three-dimensional lattices of collagenase-resistant fibrils underwent cell-mediated contraction, but the fibrils did not organize into birefringent collagen bundles. In addition, time-lapse microscopy revealed that, although cells migrated smoothly on wild-type collagen fibrils, crawling and repositioning on collagenase-resistant collagen was impaired. We conclude that type I collagen cleavage is required for efficient healing of myocardial infarcts and is critical for both dynamic positioning of collagen-producing cells and hierarchical assembly of collagen fibrils. This seemingly paradoxical requirement for collagen cleavage in fibrotic repair should be considered when designing potential strategies to inhibit matrix degradation in cardiac disease. Rapid deposition of type I collagen is critical to cardiac repair after myocardial infarction. When effectively elaborated, a type I collagen-rich matrix provides a mechanically strong network that maintains cardiac integrity, minimizes infarct expansion, and resists maladaptive remodeling.1 Elaboration of type I collagen is a multistep process that includes expression of the genes encoding pro-␣1(I) and pro-␣2(I) collagen chains, intracellular winding of the chains, and secretion of type I procollagen. Outside the cell, the propeptide termini are cleaved and the resulting triple helical type I collagen assembles into fibrils, which then cross-link and pack. Collagen deposition can be opposed by processes that degrade type I collagen. Enzymes that destroy the integrity of type I collagen by cleaving the triple helical domain are important in this regard. These include the interstitial collagenases, matrix metalloproteinase (MMP)Ϫ1, MMP-8, and MMP-13, that cleave type I collagen three fourths along the length of its triple helix. Broader-spectrum MMPs, such as MMP-2 and membrane-type (MT)1-MMP/MMP-14, also have the capacity to cleave native type I collagen.3,4 Several studies have highlighted the potential for interstitial collagenases to adversely affect the heart. Transgenic expression of MMP-1 promotes ventricular dilatation and dysfun...

Collagenase‐resistant collagen promotes mouse aging and vascular cell senescence

“…Another hallmark of aging is hypertension. We previously found that the blood pressure of young (<4 months) Col1a1 r/r mice was not different than that of wild-type control mice (Nong et al ., 2011 ). To determine whether differences existed with aged mice, blood pressures of 13-month-old mice were assessed using computerized tail-cuff plethysmography.…”

“…Such interplay could have substantial consequences for the rate of vascular deterioration. Type I collagen proteolysis has been found to impact SMC adhesion and migration (Carragher et al ., 1999 ; Li et al ., 2000 ; Fera et al ., 2004 ; Nong et al ., 2011 ). Whether collagen that is resistant to cleavage affects SMC aging is not known.…”

Peroxisome Proliferator–Activated Receptor δ Agonist GW1516 Attenuates Diet-Induced Aortic Inflammation, Insulin Resistance, and Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice

“…To further elucidate the effect of GW1516 intervention on lesion collagen, picrosirius red-stained aortic sinus sections were imaged with circular polarization microscopy to detect fibrillar collagen 22 ( Figure 2B). The collagen area fraction of lesions was 24% in HFHC-fed animals and 31% in lesions of mice subjected to GW1516 intervention (P=0.025; Figure 2F).…”

Quantification of collagen organization in histopathology samples using liquid crystal based polarization microscopy

“…We report here the first use of the birefringence mode of the LC-PolScope for quantitatively imaging fibrillar collagen in tissues, and comparing it against SHG microscopy. Previous studies [32,33] have used the LC-PolScope as a tool for looking at directionality of collagen fibers and alignment in collagen gels but not for quantitating collagen organization in pathology samples. This study proposes that the LC-PolScope could be a powerful tool for histopathology by measuring changes in collagen organization.…”