Extracellular high‐mobility group box 1 mediates pressure overload‐induced cardiac hypertrophy and heart failure

Abstract

Inflammation plays a key role in pressure overload‐induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High‐mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload‐induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild‐type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin‐embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC‐induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up‐regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload‐induced cardiac hypertrophy and cardiac dysfunction.

Angiotensin II enhances the acetylation and release of HMGB1 in RAW264.7 macrophage

“…HMGB1, a nuclear architectural protein, can also function as an inflammatory factor contributes to other pathological conditions, such as cardiovascular diseases (Li et al, 2006;Narumi et al, 2015;Zhang et al, 2016), autoimmune disease (Ardoin and Pisetsky, 2008), and cancer (Tang et al, 2007(Tang et al, , 2010. Our previous research have demonstrated that HMGB1 protein levels were elevated in the EAM heart (Su et al, 2011), meanwhile, the role of ANG II in inflammatory diseases has sparked great interest, and ANG II levels were also significantly increased in EAM (Lu et al, 2017).…”

The Janus face of HMGB1 in heart disease: a necessary update

“…In a mice model of pressure overload-induced cardiac hypertrophy by thoracic transverse aortic constriction (TAC), myocardial HMGB1 levels are upregulated because of infiltrating cells and higher expression in cardiomyocytes [107–109]. Neonatal rat cardiomyocytes (NRCM) subject to mechanical stress increase intracellular and extracellular HMGB1 in vitro [109] and this effect is abolished by fenofibrate, an inhibitor of cardiac hypertrophy [107].…”

“…Neonatal rat cardiomyocytes (NRCM) subject to mechanical stress increase intracellular and extracellular HMGB1 in vitro [109] and this effect is abolished by fenofibrate, an inhibitor of cardiac hypertrophy [107]. Hypertrophic mediators like angiotensin II or Endothelin-1 induce acetylation and nuclear translocation of HMGB1 in NRCM; conversely, maintenance of stable intracellular HMGB1 levels prevent cardiac hypertrophy [110].…”

“…Administration of BoxA in the heart reverses cardiac hypertrophy and delays heart failure (HF) induced by pressure overload, while recombinant HMGB1 aggravates it (Table 2) [109]. The ability of HMGB1 to induce cardiac hypertrophy does not involve RAGE, since Rage − / − mice still develop cardiac hypertrophy after TAC [108].…”

Cigarette smoke‐induced HMGB1 translocation and release contribute to migration and NF‐κB activation through inducing autophagy in lung macrophages

“…12 HMGB1 is present in the nuclei of almost all eukaryotic cells, especially highly expressed in macrophages, epithelial and endothelial cells, and has been implicated in several lung diseases. 12,14 Extracellular HMGB1, as a danger-associated molecular pattern (DAMP), has been shown to be involved in a variety of inflammatory diseases, 15 such as sepsis, 16 asthma 17 and arthritis. 12,14 Extracellular HMGB1, as a danger-associated molecular pattern (DAMP), has been shown to be involved in a variety of inflammatory diseases, 15 such as sepsis, 16 asthma 17 and arthritis.…”