Lindsey ML, Yoshioka J, MacGillivray C, Muangman S, Gannon J, Verghese A, Aikawa M, Libby P, Krane SM, Lee RT. 2003. Effect of a cleavage-resistant collagen mutation on left ventricular remodeling. Circulation research. 93(3):238-45. Pubmed: 12855673


Matrix metalloproteinase-mediated degradation of type I collagen may play a role in cardiac remodeling after strain or injury. To explore this hypothesis, we used mice homozygous (r/r) for a targeted mutation in Col1a1; these mice synthesize collagen I that resists collagenase cleavage at Gly975-Leu976. A total of 64 r/r and 84 littermate wild-type mice (WT) underwent experimental pressure overload by transverse aortic constriction (TAC) or myocardial infarction (MI). Echocardiographic, hemodynamic, and histological parameters were evaluated up to 12 weeks after TAC or 21 days after MI. At 4 weeks after TAC, collagen levels, wall thickness, and echocardiographic parameters were similar in the 2 groups. At 12 weeks after TAC, r/r mice had smaller LV dimensions (ESD: 2.7+/-0.2 mm WT versus 1.7+/-0.2 mm r/r, P<0.013; EDD: 3.8+/-0.2 mm WT versus 3.1+/-0.1 mm r/r, P<0.013); better fractional shortening (30+/-2% WT versus 46+/-4% r/r; P<0.013); and lower LV/body weight ratios (7.3+/-0.6 WT and 5.1+/-0.5 r/r; P<0.013). Surprisingly, these differences were not accompanied by differences in collagen accumulation, myocyte cross-sectional areas, wall thickness, or microvessel densities. Furthermore, no differences in LV remodeling assessed by echocardiography, fibrosis, or hemodynamic parameters were found between r/r and WT mice after MI. Thus, a mutation that encodes a collagenase cleavage-resistant collagen I does not affect early LV remodeling after TAC or MI, suggesting that collagen cleavage at this site is not the mechanism by which metalloproteinases mediate LV remodeling. Collagen cleavage could, however, have a role in preservation of cardiac function in late remodeling by mechanisms independent of collagen accumulation. We were not able to detect collagen cleavage fragments, and could not, therefore, rule out the possibility of collagen cleavage at additional sites.

Related Faculty

Photo of Rich Lee

Rich Lee seeks to understand heart failure and metabolic diseases that accompany human aging, and translate that understanding into therapies. Lee is an active clinician, regularly treating patients at Brigham and Women’s Hospital.

Search Menu