Abstract 10520: Cardiac-Specific Overexpression of High Mobility Group Box 1 (HMGB1) Attenuates Cardiac Dysfunction Induced By Pressure Overload
Background: High Mobility Group Box 1 (HMGB1) is as an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. In the nucleus, HMGB1 binds to DNA and is critical for proper transcriptional regulation. However, little is known about the effects of HMGB1 on heart failure. The aim of this study was to examine the impact of HMGB1 on cardiac dysfunction induced by pressure overload.
Methods and Results: We generated transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-TG) using α-myosin heavy chain promoter. There were no differences in cardiac morphology and function between wild-type (WT) and HMGB1-TG mice at basal condition. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-TG) and wild-type (WT) mice. The survival rate after TAC was significantly higher in HMGB1-TG mice compared to WT mice. Increases in heart/body weight ratio after TAC were significantly attenuated in HMGB1-TG mice compared to WT mice. Dilation of the left ventricular cavity and impaired cardiac systolic function after TAC were also attenuated in HMGB1-TG mice compared to WT mice. While aortic constriction decreased nuclear HMGB1 levels in WT mice, but not in HMGB1-TG mice, expressions of fetal genes such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were suppressed in HMGB1-TG mice.In cardiomyocytes, overexpression of HMGB1 inhibited endothelin-1(ET-1)-induced ANP and BNP promoter activity.
Conclusion: These results suggest that HMGB1 plays a cardioprotective role in pressure overload by regulating fetal cardiac genes transcription.
- © 2011 by American Heart Association, Inc.