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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Animals
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Capillaries / growth & development
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Cardiomyopathy, Dilated / genetics
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Cell Division / drug effects
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Coronary Vessels / growth & development*
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Culture Media, Conditioned / toxicity
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Endothelial Cells / drug effects
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Extracellular Matrix / metabolism*
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Fibroblasts / drug effects
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Fibrosis
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Genetic Predisposition to Disease
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Heart Failure / etiology
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Heart Failure / prevention & control
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Male
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Mice
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Mice, Knockout
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Myocardial Ischemia / complications
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Myocardial Ischemia / genetics
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Myocardial Ischemia / metabolism
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Myocardial Ischemia / prevention & control*
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Myocardial Reperfusion Injury / genetics
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Myocardial Reperfusion Injury / metabolism
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Myocardial Reperfusion Injury / prevention & control*
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Myocardium / metabolism*
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Myocardium / pathology
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Myocytes, Cardiac / metabolism*
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / genetics
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Neovascularization, Physiologic / physiology
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Paracrine Communication
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STAT3 Transcription Factor
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / physiology*
Substances
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Angiogenesis Inhibitors
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Culture Media, Conditioned
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DNA-Binding Proteins
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Trans-Activators