title: Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age.
abstract: Cytokines and inflammation have been implicated in the pathogenesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor in response to lipopolysaccharide than those with WT STAT3. Furthermore, histologic examination of the cardiomyocyte-restricted STAT3-deficient mice reveals a dramatic increase in cardiac fibrosis in aged mice. Although no overt signs of heart failure are present in young STAT3-deficient mice, they spontaneously develop heart dysfunction with advancing age. These results indicate the crucial functions of STAT3 in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Jacoby
authors.forename: April
authors.initials: A
authors.lastname: Kalinowski
authors.forename: Mu-Gen
authors.initials: MG
authors.lastname: Liu
authors.forename: Samuel S-M
authors.initials: SS
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.forename: Gui-Xuan
authors.initials: GX
authors.lastname: Chai
authors.forename: Lan
authors.initials: L
authors.lastname: Ji
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Schneider
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Fu
mesh_terms: D000375:Aging / Q000502:physiology; D000483:Alleles; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D004452:Echocardiography; D005355:Fibrosis; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D007249:Inflammation / Q000000981:diagnostic imaging / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000000981:diagnostic imaging / Q000473:pathology / Q000502:physiology*; D009206:Myocardium / Q000473:pathology*; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin