Effect of a Cleavage-Resistant Collagen Mutation on Left Ventricular Remodeling

Abstract

Abstract-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. . 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. Key Words: matrix metalloproteinases Ⅲ collagen Ⅲ left ventricular remodeling Ⅲ myocardial infarction L eft ventricular (LV) remodeling is an important cause of congestive heart failure despite the use of therapeutic agents that inhibit angiotensin II or ␤-adrenergic signaling, highlighting the need for additional understanding of remodeling events. 1 Matrix metalloproteinases (MMPs) comprise a family of enzymes that degrade extracellular matrix and may mediate cardiac remodeling. The expression of certain MMPs increases in nonischemic dilated cardiomyopathy 2 and after myocardial infarction (MI), in the presence or absence of reperfusion. 3,4 Drugs that act as "nonselective" MMP inhibitors prevent ventricular dilation in mice, rats, pigs, and rabbits. [5][6][7][8] In addition, deletion or overexpression of MMPs in mice regulates cardiac remodeling and hypertrophy. 9 -11 The potential roles of MMPs in cardiac remodeling have not yet been fully elucidated. Collagen is the most abundant protein in the body, and collagen I represents about 90% of total collagen. 12 MMP effects on collagen turnover, therefore, may explain effects on remodeling. One hypothesis is that MMPs degrade collagen fibrils and allow cardiomyocytes to "slip" and then establish new matrix attachments. 13 This hypothesis could explain the ventricular dilation that occurs in mice with transgenic overexpression of human MMP-1, 11 a collagenase, the orthologue of which is expressed only at low levels in mice. 14 Alternatively, MMP inhibition could affect the metabolism of a noncollagen molecule that is important in cardiac remodeling. A recent study of selective MMP inhibition supports this hypothesis; administration of an MMP-1 sparing MMP inhibitor prevented LV remodeling after MI in rabbits, a species that utilizes MMP-1 for collagenolysis. 8 To provide insight into these mechani...

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

“…30 Given these findings, it is noteworthy that collagen accumulation in the LV of Col1a1 r/r mice after infarction was not greater than that in control mice. This finding is consistent with a previous report 31 and probably reflects the fact that the balance of production and degradation of type I collagen after acute myocardial injury is heavily weighted to the production side. However, the current findings also establish that, despite this production bias, collagen degradation plays a key role in the infarct healing process.…”

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

“…area of the LV free wall (LVFW) endocardium and papillary muscle and the interventricular septum (IVS) base and midportion ( Figure 3C and Table 1), similar to the findings of others in this model (27). In the ABKO TAC heart, interstitial fibrosis was increased to 26% of the LVFW and IVS, or 260% to 371% greater than in the WT TAC heart (P < 0.05).…”

Regulation of matrix biology by matrix metalloproteinases

“…However, novel tools will be invaluable for understanding mechanisms of MMP regulation of ECM biology. For example a transgenic mouse carrying a mutated collagen α1 gene coding for resistance to collagenase digestion has been useful in characterizing MMPs in development and wound healing [39][40][41]. Additionally, antibodies have been developed to identify the neo-epitopes of MMP cleaved substrates.…”