title: Obesity-associated extracellular mtDNA activates central TGFβ pathway to cause blood pressure increase.
abstract: Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-β (TGFβ) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ is sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.
authors.affiliation: Department of Molecular Pharmacology, Diabetes Research Center, and Institute for Aging Research, Albert Einstein College of Medicine, New York, New York.
authors.forename: Albert
authors.initials: A
authors.lastname: Alé
authors.affiliation: Department of Molecular Pharmacology, Diabetes Research Center, and Institute for Aging Research, Albert Einstein College of Medicine, New York, New York.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pharmacology, Diabetes Research Center, and Institute for Aging Research, Albert Einstein College of Medicine, New York, New York.
authors.forename: Cheng
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Molecular Pharmacology, Diabetes Research Center, and Institute for Aging Research, Albert Einstein College of Medicine, New York, New York dongsheng.cai@einstein.yu.edu.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure / Q000276:immunology*; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D059305:Diet, High-Fat; D004149:Dioxoles / Q000494:pharmacology; D006973:Hypertension / Q000209:etiology / Q000276:immunology*; D007031:Hypothalamus / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000276:immunology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D020542:Third Ventricle; D016212:Transforming Growth Factor beta / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004272:DNA, Mitochondrial; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D011333:Pro-Opiomelanocortin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: brain; hypertension; hypothalamus; inflammation; mitochondrial DNA; transforming growth factor-β