Absence of Type VI Collagen Paradoxically Improves Cardiac Function, Structure, and Remodeling After Myocardial Infarction

Abstract

Rationale We previously reported that type VI collagen deposition increases in the infarcted myocardium in vivo. To date, a specific role for this non-fibrillar collagen has not been explored in the setting of myocardial infarction (MI). Objective To determine whether deletion of type VI collagen in an in vivo model of post-MI wound healing would alter cardiac function and remodeling in the days to weeks after injury. Methods and Results Wild type (WT) and Col6a1-/- mice were subjected to MI followed by serial echocardiographic and histological assessments. At 8 weeks post-MI, infarct size was significantly reduced, ejection fraction was significantly preserved (43.9 ± 3.3% vs. 29.1 ± 4.3% for WT) and left ventricular (LV) chamber dilation was attenuated in the Col6a1-/- MI group (25.8 ± 7.9% increase vs. 62.6 ± 16.5% for WT). The improvement in cardiac remodeling was evident as early as 10 days post-MI in the Col6a1-/- mice. Myocyte apoptosis within the infarcted zones was initially greater in the Col6a1-/- group 3 days post-MI but by day 14 this was significantly reduced. Collagen deposition was also reduced in the infarcted and remote areas of the Col6a1-/- hearts. The reductions in chronic myocyte apoptosis and fibrosis are critical events leading to improved long-term remodeling and functional outcomes. Conclusions These unexpected results demonstrate for the first time that deletion of type VI collagen in this knockout model plays a critical protective role following MI by limiting infarct size, chronic apoptosis, aberrant remodeling and fibrosis leading to preservation of cardiac function.

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

“…S6). Notably, Col6 is not readily detected in uninjured heart tissue confirming that Col6 is induced following injury, as previously described (23). Taken together, these observations suggest Porcn inhibitors promote functional recovery of heart tissue primarily by mitigating scarring that may in part be attributable to loss in expression of the anti-regenerative molecule Col6.…”

“…For example, the secreted Wnt/β-catenin signaling antagonist Dkk3 suppresses maladaptive remodeling of infarcted tissue in mice and protects against cardiac dysfunction after injury (22). The decreased expression of the Col6 subunit (Col6a3) is also notable, given that Col6 has been shown to suppress heart regeneration in injured murine heart tissue (23). Animals null for COL6A1 show a marked improvement in heart function and decreased scarring following left anterior descending (LAD) ligation, as in the case of WNT-974-treated animals.…”

Collagen VI at a glance

“…For instance, in the heart, ColVI is secreted by interstitial fibroblasts, and although it has been reported to be overexpressed in the infarcted myocardium, studies in Col6a1 −/− mice led to the paradoxical finding that lack of ColVI in fact improves cardiac function, structure and remodeling after myocardial infarction (Luther et al, 2012). In tendons, the strong mechanical properties are largely provided by uniaxially grouped collagen fibrils.…”

Annexin A2 mediates collagen VI secretion, pulmonary elasticity, and bronchial epithelial cell apoptosis

“…Interestingly, soluble COL6 appears to prevent apoptosis of serum-starved fibroblasts by suppressing the pro-apoptotic protein, Bax (Rühl et al, 1999). In avian corneal fibroblasts, cell viability depends specifically on the interaction between matrix-associated COL6 and cellmembrane-associated b1 integrins (Howell and Doane, 1998), and COL6 also appears to protect chondrocytes, neurons and cardiac myocytes from apoptosis due to chemical inducers, ultraviolet irradiation or early, but not late, tissue infarction, respectively (Cheng et al, 2011;Luther et al, 2012;Peters et al, 2011). In Col6a1 2/2 mice, myofibers undergo apoptotic cell death in a process thought to reflect opening of the cyclosporine-A-sensitive, mitochondrial permeability transition pore, which might be triggered by integrin-mediated induction of reactive oxygen species or defective regulation of autophagy (Grumati et al, 2010;Irwin et al, 2003).…”