title: Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload.
abstract: The cardiac pathological response to sustained pressure overload involves myocyte hypertrophy and dysfunction along with interstitial changes such as fibrosis and reduced capillary density. These changes are orchestrated by mechanical forces and factors secreted between cells. One such secreted factor is TGF-β, which is generated by and interacts with multiple cell types. Here we have shown that TGF-β suppression in cardiomyocytes was required to protect against maladaptive remodeling and involved noncanonical (non-Smad-related) signaling. Mouse hearts subjected to pressure overload and treated with a TGF-β-neutralizing Ab had suppressed Smad activation in the interstitium but not in myocytes, and noncanonical (TGF-β-activated kinase 1 [TAK1]) activation remained. Although fibrosis was greatly reduced, chamber dysfunction and dilation persisted. Induced myocyte knockdown of TGF-β type 2 receptor (TβR2) blocked all maladaptive responses, inhibiting myocyte and interstitial Smad and TAK1. Myocyte knockdown of TβR1 suppressed myocyte but not interstitial Smad, nor TAK1, modestly reducing fibrosis without improving chamber function or hypertrophy. Only TβR2 knockdown preserved capillary density after pressure overload, enhancing BMP7, a regulator of the endothelial-mesenchymal transition. BMP7 enhancement also was coupled to TAK1 suppression. Thus, myocyte targeting is required to modulate TGF-β in hearts subjected to pressure overload, with noncanonical pathways predominantly affecting the maladaptive hypertrophy/dysfunction.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Koitabashi
authors.forename: Thomas
authors.initials: T
authors.lastname: Danner
authors.forename: Ari L
authors.initials: AL
authors.lastname: Zaiman
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Janelle
authors.initials: J
authors.lastname: Rowell
authors.forename: Joseph
authors.initials: J
authors.lastname: Mankowski
authors.forename: Dou
authors.initials: D
authors.lastname: Zhang
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000150:complications / Q000503:physiopathology; D055419:Bone Morphogenetic Protein 7 / Q000502:physiology; D055513:Connective Tissue Growth Factor / Q000502:physiology; D003251:Constriction, Pathologic / Q000150:complications / Q000503:physiopathology; D003326:Coronary Circulation; D055785:Gene Knockdown Techniques; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D008026:Ligation; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D011312:Pressure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D055419:Bone Morphogenetic Protein 7; D055513:Connective Tissue Growth Factor; D020930:MAP Kinase Kinase Kinases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7; C526318:CCN2 protein, mouse; C508961:Tgfb1 protein, mouse; C525820:bmp7 protein, mouse