title: p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload.
abstract: The rates of death and disability caused by severe heart failure are still unacceptably high. There is evidence that the sterile inflammatory response has a critical role in the progression of cardiac remodeling in the failing heart. The p53 signaling pathway has been implicated in heart failure, but the pathological link between p53 and inflammation in the failing heart is largely unknown. Here we demonstrate a critical role of p53-induced inflammation in heart failure. Expression of p53 was increased in cardiac endothelial cells and bone marrow cells in response to pressure overload, leading to up-regulation of intercellular adhesion molecule-1 (ICAM1) expression by endothelial cells and integrin expression by bone marrow cells. Deletion of p53 from endothelial cells or bone marrow cells significantly reduced ICAM1 or integrin expression, respectively, as well as decreasing cardiac inflammation and ameliorating systolic dysfunction during pressure overload. Conversely, overexpression of p53 in bone marrow cells led to an increase of integrin expression and cardiac inflammation that reduced systolic function. Norepinephrine markedly increased p53 expression in endothelial cells and macrophages. Reducing β2-adrenergic receptor expression in endothelial cells or bone marrow cells attenuated cardiac inflammation and improved systolic dysfunction during pressure overload. These results suggest that activation of the sympathetic nervous system promotes cardiac inflammation by up-regulating ICAM1 and integrin expression via p53 signaling to exacerbate cardiac dysfunction. Inhibition of p53-induced inflammation may be a novel therapeutic strategy for heart failure.
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Katsuumi
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Jiao
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Suda
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan; PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan. Electronic address: t_minamino@yahoo.co.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
mesh_terms: D000818:Animals; D040881:CD11a Antigen / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006333:Heart Failure / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D009638:Norepinephrine / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction; D013599:Systole; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D017725:Ventricular Pressure
chemical_list: D040881:CD11a Antigen; C090509:Icam1 protein, mouse; D017382:Reactive Oxygen Species; D018343:Receptors, Adrenergic, beta-2; D016159:Tumor Suppressor Protein p53; D018799:Intercellular Adhesion Molecule-1; D051736:Proto-Oncogene Proteins c-mdm2; D009638:Norepinephrine
keywords: Bone marrow cells; Endothelial cells; Heart failure; Inflammation