Abstract 13010: Deletion of Tenascin C Attenuates Pressure Overload Induced Cardiac Dilation and Contractile Dysfunction
Introduction The extracellular matrix protein tenascin C (TnC) is highly expressed during embryogenesis. In adult tissues, TnC is not expressed under physiologic conditions but strongly induced in stressed, inflamed and remodeled tissues. Growing evidence linked TnC with development and complications of cardiovascular disease. We hypothesized that the absence of TnC would protect the heart from pressure overload induced cardiac dysfunction.
Methods Transverse aortic constriction (TAC, n=10-12/group) or Sham (n=6-7/group) operations were performed in male C57BL/6N wild type (WT) and TNC knockout (KO) mice. After 1 or 6 weeks, echocardiographic measurements of left ventricular (LV) parameters and standard methods for cardiac gene expression, collagen coloration and immunolocalization were employed.
Results In WT mice, TAC led to re-expression and protein deposition of TnC in perivascular and interstitial areas with a peak after 1 week (6.5% of heart surface vs 0% in Sham). Echocardiographic measurements after 6 weeks of TAC exhibited significantly increased of ventricular hypertrophy in both WT+TAC and KO+TAC compared to Sham (LV posterior wall dimension WT+TAC:0.102±0.006 vs Sham: 0.078±0.003cm, p<0.01; KO+TAC:0.092±0.002 vs Sham:0.072±0.005cm, p<0.5). However, cardiac dilation induced by TAC was observed in WT but not in KO mice (LV internal diastolic dimension in cm; WT TAC: 0.487±0.012 vs Sham: 0.375±0.009cm, p<0.001; KO TAC 0.430 ± 0.011 vs Sham 0.407±0.011). Myocardial contractility was also less reduced in KO+TAC than in WT+TAC (fractional shortening 23.4±1.5 vs 13.9±2 %, p<0.001). In parallel, collagen deposition was lower in KO+TAC than in WT+TAC (2.1±0.3 vs 3.2±0.4%, p<0.5). Strikingly, up regulation of inflammatory cytokines and chemokines genes (IL-6, CXCL10, CCL2, CCL5, CX3CL1) induced by TAC in WT mice was completely abolished in KO mice. Heart deposition of TnC was clearly colocalized with area enriched in inflammatory cell marker CD45 and interestingly, the deletion of TnC prevented macrophage recruitment induced by TAC.
Conclusions. In conclusion, the absence of TnC attenuates the development of heart failure after pressure overload through possibly down regulation of inflammatory response and leukocyte recruitment.
- © 2012 by American Heart Association, Inc.