title: Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury.
abstract: The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses such as proliferation and apoptosis. To elucidate its role in the heart, we generated mice harboring a cardiomyocyte-restricted knockout of STAT3 using Cre/loxP-mediated recombination. STAT3-deficient mice developed reduced myocardial capillary density and increased interstitial fibrosis within the first 4 postnatal months, followed by dilated cardiomyopathy with impaired cardiac function and premature death. Conditioned medium from STAT3-deficient cardiomyocytes inhibited endothelial cell proliferation and increased fibroblast proliferation, suggesting the presence of paracrine factors attenuating angiogenesis and promoting fibrosis in vitro. STAT3-deficient mice showed enhanced susceptibility to myocardial ischemia/reperfusion injury and infarction with increased cardiac apoptosis, increased infarct sizes, and reduced cardiac function and survival. Our study establishes a novel role for STAT3 in controlling paracrine circuits in the heart essential for postnatal capillary vasculature maintenance, interstitial matrix deposition balance, and protection from ischemic injury and heart failure.
authors.affiliation: Department of Cardiology, Medical School Hannover, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
authors.forename: Andres
authors.initials: A
authors.lastname: Hilfiker
authors.forename: Martin
authors.initials: M
authors.lastname: Fuchs
authors.forename: Karol
authors.initials: K
authors.lastname: Kaminski
authors.forename: Arnd
authors.initials: A
authors.lastname: Schaefer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.forename: Anja
authors.initials: A
authors.lastname: Hillmer
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmiedl
authors.forename: Zhaoping
authors.initials: Z
authors.lastname: Ding
authors.forename: Edith
authors.initials: E
authors.lastname: Podewski
authors.forename: Eva
authors.initials: E
authors.lastname: Podewski
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000254:growth & development; D002311:Cardiomyopathy, Dilated / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D003331:Coronary Vessels / Q000254:growth & development*; D017077:Culture Media, Conditioned / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019899:Paracrine Communication; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D020533:Angiogenesis Inhibitors; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators