Abstract 11806: High-Mobility Group Box 1 Aggravates Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure
Introduction: Inflammatory response is involved in pressure overload-induced cardiac remodeling, but the mechanisms have not yet been fully elucidated.
Hypothesis: High-mobility group box 1 (HMGB1), which is of crucial importance in inflammatory response, may participate in pressure overload-induced cardiac hypertrophy and heart failure.
Methods: Pressure overload was imposed on the heart of adult male wild-type C57BL/6J mice by transverse aortic constriction (TAC), while 200ng recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the left ventricular wall. Transthoracic echocardiography, detection of proteins and genes expression in myocardium were performed at 2 and 4 weeks after the operation. Sections for histological analyses were generated from paraffin embedded hearts. Moreover, cardiac myocytes were cultured and given sustained mechanical stress and/or HMGB1 treatment before signaling pathways detection under the blockage of receptor for advanced glycation end products (RAGE) and Toll-like receptor (TLR)-4.
Results: HMGB1 expression in myocardium was significantly increased after TAC, which was accompanied by its translocation from nucleus to intercellular space. Exogenous HMGB1 aggravated TAC-induced cardiac hypertrophy and heart failure, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Moreover, TAC-induced cardiac remodeling could be partially reversed by HMGB1 box A. Similarly, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. Both mechanical stress and HMGB1 treatment could activate p38, extracellular signal-regulated kinase (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) in the cells partially via RAGE receptor, on which the specific synergistic effect of the two treatments were observed.
Conclusions: This study indicates that the activation of HMGB1 in myocardium under pressure overload may promote cardiac hypertrophy and worsen cardiac function partially through RAGE and mitogen-activated protein kinases signaling pathway. Meanwhile, blockage of HMGB1 might represent a novel therapeutic strategy in pressure overload-induced cardiac injury.
Author Disclosures: L. Zhang: None. M. Liu: None. H. Jiang: None. Y. Yu: None. S. Zhang: None. J. Wu: None. Q. Cao: None. P. Yu: None. A. Sun: None. Y. Zou: None. J. Ge: None.
- © 2014 by American Heart Association, Inc.