Abstract 19233: Hmgb1 Ameliorates Cardiac Function and Remodelling and Markedly Enhances miR-206 Expression in Chronically Failing Hearts
Background: HMGB1 (H) injection into the mouse heart, acutely after myocardial infarction (MI), improves left ventricular (LV) function and prevents myocardial remodelling. Here, we examined the effect of H in chronically failing hearts and miRNAs potential role in H-mediated response.
Methods and Results: HMGB1 (H; 200 ng) or denatured HMGB1 (C) were injected in the peri-infarcted region of mouse failing hearts 3 weeks after MI. Four weeks after treatment, Ejection Fraction by echocardiography was 9% higher in H than in C mice (p<0.001); further, H enhanced LV developed pressure (LVDP; 73.2±8.3 vs 64.1±7 mmHg; p<0.01) and lowered LV end-diastolic pressure (LVEDP; 16.8±3.2 vs 19.6±3.2 mmHg; p<0.05). LV remodeling was significantly attenuated in H mice as indicated by 23% (p<0.05) reduction in LV volume and 48% (p<0.05) increase in infarcted wall thickness (p<0.05). Importantly, HMGB1 affected infarct scar formation: HMGB1-injected hearts displayed 19% reduced collagen deposition (p<0.0001) and enhanced MMP2, MMP9 and MMP13 activity by zymography. Importantly, H-treated hearts exhibited evidence of regeneration: an increase in newly formed myocytes (16.53×106 vs 1.35×106; average volume 579 ±113 μm3 vs 324 ±183; p<0.0004), and in arteriole length density (14.5±6.5 vs 7±3 mm/mm3; p<0.05) was detected. miR-206 expression 24 days after MI was 4-fold higher than in sham operated mice (p<0.05); further, 3 days after H treatment, miR-206 increased 5-fold (p<0.03) compared to C whereas miR−29a, −29b, −29c, −1, −21, −133a and −133b were not modulated by H. Fibronectin (Fn) and Tissue Inhibitor of Metalloproteases 3 (TIMP3) were identified as potential miR-206 targets by TargetScan prediction analysis. Real Time PCR demonstrated Fn and TIMP3 downregulation in H-treated hearts. In agreement with this observation, in cultured cardiac fibroblasts, miR-206 overexpression inhibited and miR-206 antagomir enhanced Fn and TIMP3 mRNA by Real Time PCR.
Conclusion: H injected into chronically failing hearts enhances LV function, tissue regeneration and attenuates LV remodeling; these effects are associated with miR-206 overexpression and miR-206 -mediated reduction of Fn and TIMP mRNA.
- © 2010 by American Heart Association, Inc.